Method of treating a patient having precancerous lesions with quinazoline derivatives

ABSTRACT

Derivatives of Quinazoline are useful for the treatment of patients having precancerous lesions. These compounds are also useful to inhibit growth of neoplastic cells.

[0001] This application is a Continuation of prior U.S. application Ser.No. 09/055,829 filed Apr. 6, 1998, entitled “Method of Treating aPatient Having Precancerous Lesions with Quinazoline Derivatives,” whichis a continuation of prior U.S. application Ser. No. 08/477,227 filedJun. 7, 1995, entitled “Method of Treating a Patient Having PrecancerousLesions with Quinazoline Derivatives.”

TECHNICAL FIELD

[0002] This invention relates to methods for treatment or prevention ofprecancerous lesions.

BACKGROUND OF THE INVENTION

[0003] Each year in the United States alone, untold numbers of peopledevelop precancerous lesions. These lesions exhibit a strong tendency todevelop into malignant tumors, or cancer. Such lesions include lesionsof the breast (that can develop into breast cancer), lesions of the skin(that can develop into malignant melanoma or basal cell carcinoma),colonic adenomatous polyps (that can develop into colon cancer), andother such neoplasms. Compounds which prevent or induce the remission ofexisting precancerous or cancerous lesions or carcinomas would greatlyreduce illness and death from cancer.

[0004] Approximately 60,000 people die from colon cancer, and over150,000 new cases of colon cancer are diagnosed each year. For theAmerican population as a whole, individuals have a six percent lifetimerisk of developing colon cancer, making it the second most prevalentform of cancer in the country. Colon cancer is also prevalent in WesternEurope. It is believed that increased dietary fat consumption isincreasing the risk of colon cancer in Japan.

[0005] In addition, the incidence of colon cancer reportedly increaseswith age, particularly after the age of 40. Since the mean ages ofpopulations in America and Western Europe are increasing, the prevalenceof colorectal cancer should increase in the future.

[0006] To date, little progress has been made in the prevention andtreatment of colorectal cancer, as reflected by the lack of change inthe five-year survival rate over the last few decades. The only cure forthis cancer is surgery at an extremely early stage. Unfortunately, mostof these cancers are discovered too late for surgical cure. In manycases, the patient does not experience symptoms until the cancer hasprogressed to a malignant stage.

[0007] In view of these grim statistics, efforts in recent years haveconcentrated on colon cancer prevention. Colon cancer usually arisesfrom pre-existing benign neoplastic growths known as polyps. Preventionefforts have emphasized the identification and removal of colonicpolyps. Polyps are identified by x-ray and/or colonoscopy, and usuallyremoved by devices associated with the colonoscope. The increased use ofcolon x-rays and colonoscopies in recent years has detected clinicallysignificant precancerous polyps in four to six times the number ofindividuals per year that acquire colon cancer. During the past fiveyears alone, an estimated 3.5 to 5.5 million people in the United Stateshave been diagnosed with adenomatous colonic polyps, and it is estimatedthat many more people have or are susceptible to developing thiscondition, but are as yet undiagnosed. In fact, there are estimates that10-12 percent of people over the age of 40 will form clinicallysignificant adenomatous polyps.

[0008] Removal of polyps has been accomplished either with surgery orfiber-optic endoscopic polypectomy—procedures that are uncomfortable,costly (the cost of a single polypectomy ranges between $1,000 and$1,500 for endoscopic treatment and more for surgery), and involve asmall but significant risk of colon perforation. Overall, about $2.5billion is spent annually in the United States in colon cancer treatmentand prevention.

[0009] As indicated above, each polyp carries with it a chance that itwill develop into a cancer. The likelihood of cancer is diminished if apolyp is removed. However, many of these patients demonstrate apropensity for developing additional polyps in the future. They must,therefore, be monitored periodically for the rest of their lives forpolyp reoccurrence.

[0010] In most cases (i.e. the cases of so-called common sporadicpolyps), polyp removal will be effective to reduce the risk of cancer.In a small percentage of cases (i.e. the cases of the so-calledpolyposis syndromes), removal of all or part of the colon is indicated.The difference between common sporadic polyps and polyposis syndromes isdramatic. Common sporadic polyp cases are characterized by relativelyfew polyps, each of which can usually be removed leaving the colonintact. By contrast, polyposis syndrome cases can be characterized bymany (e.g. hundreds or more) of polyps—literally covering the colon insome cases—making safe removal of the polyps impossible short ofsurgical removal of the colon.

[0011] Because each polyp carriers with it the palpable risk ofcancerous development, polyposis syndrome patients invariably developcancer if left untreated. Surgical removal of the colon is theconventional treatment. Many of these patients have undergone a severechange in lifestyle as a result of the disfiguring surgery. Patientshave strict dietary restrictions, and many must wear ostomy appliancesto collect their intestinal wastes.

[0012] The search for drugs useful for treating and preventing cancer isintensive. Indeed, much of the focus of cancer research today is on theprevention of cancer because therapy is often not effective and hassevere side effects. Cancer prevention is important for recovered cancerpatients who retain a risk of cancer reoccurrence. Also, cancerprevention is important for people who have not yet had cancer, but havehereditary factors that place them at risk of developing cancer. Withthe development of new diagnostic screening technologies, it is possibleto identify those with high risk factors, such as the potential forpolyposis syndrome, who would greatly benefit from chemopreventivedrugs. Therefore, finding such anti-cancer drugs that can be used forprolonged preventive use is of vital interest to many people.

[0013] One way to find such drugs is to screen thousands of compoundsfor the same biological activity found in known chemopreventive andchemotherapeutic drugs. Most such drugs are now believed to kill cancercells by inducing apoptosis, or as sometimes referred to as “programmedcell death.” Apoptosis naturally occurs in virtually all tissues of thebody, and especially in self-renewing tissues such as bone marrow, gut,and skin. Apoptosis plays a critical role in tissue homeostasis, thatis, it ensures that the number of new cells produced are correspondinglyoffset by an equal number of cells that die. For example, the cells inthe intestinal lining divide so rapidly that the body must eliminatecells after only three days in order to prevent the overgrowth of theintestinal lining.

[0014] Recently, scientists have realized that abnormalities ofapoptosis can lead to the formation of precancerous lesions andcarcinomas. Also, recent research indicates that defects in apoptosisplays a major role in other diseases in addition to cancer.Consequently, compounds that modulate apoptosis could be used to preventor control cancer, as well as used in the treatment of other diseases.

[0015] Unfortunately, even though known chemotherapeutic drugs mayexhibit such desirable apoptotis effects, most chemotherapeutic drugshave serious side effects that prohibit their long term use, or use inotherwise healthy individuals with precancerous lesions. These sideeffects, which are a result of the high levels of cytotoxicity of thedrugs, include hair loss, weight loss, vomiting and bone marrow immunesuppression. Therefore, there is a need to identify new drug candidatesfor therapy that do not have such serious side effects in humans.

SUMMARY OF THE INVENTION

[0016] This invention is a method of treating patients with precancerouslesions or neoplasms by administering a pharmacologically effectiveamount of a compound of Formula I below to a patient in need of suchtreatment. Such compositions are effective in modulating apoptosis, andeliminating and inhibiting precancerous lesions, and neoplastic cells.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

[0017] As discussed above, this invention is a method of treating apatient with precancerous lesions or neoplasms by administering apharmacologically effective amount of the quinazoline derivativerepresented by the following formula (I), or the pharmacologicallyacceptable salt thereof;

[0018] wherein R¹, R², R³ and R⁴, each of which may be the same ordifferent from one another, represent each a hydrogen atom, a halogenatom, a alkyl group having 1 to 6 carbon atoms, a alkoxy group having1to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, acyano group, an acylamino group, or a carboxyl group which may beprotected, or two of R¹, R², R³ and R⁴ may together form methylenedioxy,ethylenedioxy, or a phenyl ring;

[0019] R5 and R6, each of which may be the same or different, areselected from a hydrogen atom, a lower alkyl group having 1 to 6 carbonatoms, a hydroxylalkyl group having from 1 to 6 carbon atoms, anaminoalkyl group having from 1 to 6 carbon atoms, a carboxyalkyl groupwhich may be protected, alkylcarbamoyl group having 2 to 8 carbon atoms,a 1,3-benzdioxolyalkyl group or a 1,4-benzdioxylalkyl group, or furtherR5 and R6 may form a ring which may contain another nitrogen atom and oroxygen atom together with the nitrogen atom to which they are bonded,and which may be substituted;

[0020] R7 is selected from a hydrogen atom, a alkyl group having 1 to 6carbon atoms, an acyl group, a alkoxyalkyl group having 2 to 8 carbonatoms, a carboxyalkyl group having 2 to 8 carbon atoms which may beprotected or a hydroxyalkyl group having 2 to 8 carbon atoms;

[0021] R8 is selected from a hydrogen atom, a hydroxyl group, a carboxylgroup which may be protected, a cyano group, an acyl group, a heteroarylgroup which may be substituted or a benzyl group which may besubstituted, said substitutions, which may be the same or different, areselected from a hydrogen atom, a halogen atom, a hydroxyl group, anamino group, a nitro group, a alkyl group having from 1 to 6 carbonatoms, a alkoxy group having from 1 to 6 carbon atoms, a alkoxyalkylgroup having from 2 to 8 carbon atoms, a alkenyl group having from 2 to8 carbon atoms, an acyl group an acylamino group, an alkylsulfonylaminogroup, a hydroiminoalkyl group, an alkyloxy-carbonylamino group, analkyloxycarbonyloxy group or a heteroaryl group which may besubstituted: or two of said substitutions may together form a saturatedor unsaturated ring which may contain a nitrogen, a sulfer atom or anoxygen atom; and

[0022] Y is a group represented by the formula —(CH2) q— (wherein q is 0or an integer of 1 to 8), when q is an integer of 1 to 8, each carbonatom may have from 1 to 2 substituents, or Y is a group represented bythe formula:

[0023] Preferably, R1, R2, R3, and R4, each of which may be the same ordifferent from one another, are selected from a hydrogen atom, a cyanogroup, a halogen atom, or a lower alkoxy group. More preferably, one ofR1, R2, R3 and R4 is a cyano group, a halogen atom or a methoxy group.Still more preferably, R2 is a halogen atom. Most preferably, R2 is achlorine atom, and R1, R3 and R4 are hydrogen atoms.

[0024] It is preferred that Y is a group represented by the formula—(CH₂)q—, wherein q is an integer of 1 to 8. When such occurs, R8 isbenzyl group which may be substituted, said substitutions, each of whichmay be the same or different, are each selected from a hydrogen atom, ahalogen atom, a hydroxy group, an amino group, a nitro group, a loweralkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a loweralkenyl group, an acyl group, an acylamino group, an alkylsulfonylaminogroup, a hydroxyiminoalkyl group, an alkyloxycarbonylamino group, analkyloxycarbonyloxy group or a heteroaryl group which may besubstituted, or two of the substitutions may together form a saturatedor unsaturated ring which may contain a nitrogen atom, a sulfer atom oran oxygen atom; and q is an integer of 1 to 8. However, it is preferredthat R8 is a group represented by the formula:

[0025] In which case, preferably, R7 is a hydrogen atom, and R5 and R6form a ring represented by the formula:

[0026] wherein R9 is selected from a hydroxyl group which may beprotected, a halogen atom, a alkyl group having 1 to 8 carbon atoms, alower alkoxy group, a carboxyl group which may be protected, ahydroxyalkyl group, a carboxyalkyl group and a heteroacyl group.

[0027] Also, R5 and R6 may form a substituted ring structure representedby the formula:

[0028] wherein Z is represented by the formula:

[0029] wherein X is S or O;

[0030] or Z is a cycloalkyl having 3 to 8 ring carbon atoms or acycloalkenyl having 4 to 8 ring carbon atoms;

[0031] wherein R10 and R11 are independently selected from hydrogen,amino, lower alkyl, lower alkoxy and lower alkylthio; and X is eithersulfur or oxygen.

[0032] Also, R5 and R6 may form a substituted ring structure representedby the formula:

[0033] wherein A represents a group selected from the following (i) and(ii):

[0034] (i) R12—CO—:

[0035] wherein R12 represents a lower alkyl group; phenyl substitutedwith a halogen atom, methoxy group or methanesulfonyl group; a styrylgroup unsubstituted or ring substituted with a halogen atom, methoxygroup or 3,4-methylenedioxy group or 2-furyl group; and

[0036] (ii) R13—:

[0037] wherein R13 represents a lower alkyl group of C1-C4; benzyl groupsubstituted with a halogen atom or methoxy group; or B—(2-pyridyl)ethylgroup.

[0038] “Alkyl group” refers to straight or branched chain C₁-C₁₂ groupssuch as methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl and amyl.“Alkoxy group” refers to hydroxy-substituted alkyl groups such asmethoxy, ethoxy, propoxy, butoxy and amyloxy. “Alkoxycarbonyl group”refers to carbonyl-substituted alkoxy groups such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, amyloxycarbonyl, etc.“Alkylcarbonyl group” refers to carbonyl-substituted alkyl groups suchas acetyl, propionyl, butyryl or others. “Halogen” refers to fluorine,chlorine, bromine and iodine.

[0039] The pharmacologically acceptable salt includes inorganic acidsalts such as hydrochloride, hydrobromide, sulfate and phosphate;organic acid salts such as acetate, maleate, tartrate, methanesulfonate,benzenesulfonate and toluenesulfonate; and amino acid salts such asargininate, aspartate and glutamate. Further, some of the compounds mayform metal salts such as Na, K, Ca or Mg, and the pharmacologicallyacceptable salt of formula (I) also includes these metal salts.

[0040] Although the compound of formula I may be present as variousisomers including geometrical isomers, i.e., cis-isomer andtrans-isomer. and optical isomers, i.e., d-isomer and 1-isomer dependingupon the kinds and combination of the substituents, it is needless tosay that the compounds include all of the isomers.

[0041] As used herein, the term “precancerous lesion” refers to lesionsthat exhibit histologic changes which are associated with an increasedrisk of cancer development. Examples include adenomatous polyps of thecolon, dysplastic nevi of the skin and atypical hyperplasia of thebreasts. Certain syndromes that commonly display precancerous lesionsare also referred to by the term “precancerous” including dysplasticnevus syndrome and the colonic polyposis syndromes. “Precancerous”refers to these lesions or syndromes of various tissues whether or notthe lesions are clinically identifiable.

[0042] As used herein, the term “carcinomas” refers to lesions which arecancerous. Examples include malignant melanomas, breast cancer, andcolon cancer.

[0043] As used herein, the term, “neoplasm” refers to both precancerousand cancerous lesions.

[0044] As used herein, the term “halo” or “halogen” refers to chloro,bromo, fluoro and iodo groups, and the term “alkyl” refers to straight,branched or cyclic alkyl groups.

[0045] Compounds of formula I may be formulated into compositionstogether with pharmaceutically acceptable carriers for injection, oraladministration in solid or liquid form, or for rectal administration,although carriers for oral administration are most preferred.

[0046] Pharmaceutically acceptable carriers for oral administrationinclude capsules, tablets, pills, powders, troches and granules. In suchsolid dosage forms, the carrier can comprise at least one inert diluentsuch as sucrose, lactose or starch. Such carriers can also comprise, asis normal practice, additional substances other than diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, troches and pills, the carriers may also comprise bufferingagents. Carriers such as tablets, pills and granules can be preparedwith enteric coatings on the surfaces of the tablets, pills or granules.Alternatively, the enterically coated compound can be pressed into atablet, pill, or granule, and the tablet, pill or granules foradministration to the patient. Preferred enteric coatings include thosethat dissolve or disintegrate at colonic pH such as shellac or EudragetS.

[0047] Pharmaceutically acceptable carriers include liquid dosage formsfor oral administration, e.g. pharmaceutically acceptable emulsions,solutions, suspensions, syrups and elixirs containing inert diluentscommonly used in the art, such as water. Besides such inert diluents,compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring andperfuming agents.

[0048] Pharmaceutically acceptable carriers for rectal administrationare preferably suppositories which may contain, in addition to thecompounds of Formula I, excipients such as cocoa butter or a suppositorywax.

[0049] The pharmaceutically acceptable carrier and compounds of FormulaI are formulated into unit dosage forms for administration to a patient.The dosage levels of active ingredient (i.e. compounds of Formula I) inthe unit dosage may be varied so as to obtain an amount of activeingredient effective to achieve polyp-eliminating activity in accordancewith the desired method of administration (i.e. oral or rectal). Theselected dosage level therefore depends upon the nature of the activecompound administered, the route of administration, the desired durationof treatment, and other factors. If desired, the unit dosage may be suchthat the daily requirement for active compound is in one dose, ordivided among multiple doses for administration, e.g. two to four timesper day.

[0050] In another form, the invention is a method of inhibiting thegrowth of neoplastic cells by exposing them to an effective amount ofthe compound of formula [I] above.

[0051] In still another form, the invention is a method of inducingapoptosis in human cells by exposing those cells to an effective amountof the compound of formula [I] above where such cells are sensitive tothis compound.

[0052] Additionally, in yet another form, the invention is a method oftreating a patient having a disease which would benefit from regulationof apoptosis by treating the patient with an effective amount of thecompound of formula [I] above. The regulation of apoptosis is believedto play an important role in diseases associated with abnormalities ofcellular growth patterns such as benign prostatic hyperplasia,neurodegenerative diseases such as Parkinson's disease, autoimmunediseases including multiple sclerosis and rheumatoid arthritis,infectious diseases such as AIDS, and other diseases, as well.

[0053] The foregoing may be better understood from the followingexamples, which are presented for purposes of illustration and are notintended to limit the scope of the invention. As used in the followingexamples, the references to substituents such as R, R¹, R² etc., referto the corresponding compounds and substituents in the Formula above.

[0054] Preferable specific examples of the compound will now bedescribed in order to facilitate the understanding of the presentinvention, though it is needless to say that the compounds of thepresent invention are not limited to these examples.

Preparation Process

[0055] Representative processes for the preparation of the compoundsutilized in the present invention will now be described below. Arepresentative quinazoline skeleton as shown following is useful torepresent the processes.

[0056] Though compounds having a quinazoline skeleton are mainlydescribed in the following explanation, the following explanation can beapplied for compounds having a skeleton other than the quinazolineskeleton.

Preparation Process 1

[0057] When R⁵ is a hydrogen atom, a halogen atom or a group selectedfrom among those which are directly bonded to the quinazoline skeletonthrough a carbon atom in the general formula (I), a compound similar tothe general formula (I) can also be prepared by the following process:

[0058] (in a series of formulas, R⁵ _(a) is a hydrogen atom, a halogenatom or a group selected from among those which are directly bonded tothe quinazoline skeleton through a carbon atom in R⁵ described above;and R¹, R², R³ and R⁴ are each as defined above.

[0059] That is, this process is one for preparing a quinazolinederivative represented by the general formula (III) by reacting aquinazoline derivative represented by the general formula (II) withphosphorus oxychloride or by reacting it with phosphorus oxychloride inthe presence of phosphorus pentachloride under heating.

Preparation Process 2

[0060] When R⁵ is a group selected from among a hydrogen atom, a halogenatom, a group represented by the formula:

[0061] (wherein R⁸ and m are each as defined above), a group representedby the formula —O—R⁹ (wherein R⁹ represents a hydroxyalkyl group whichmay be protected, a carboxyalkyl group which may be protected or abenzyl group), a heteroaryl group which may be substituted and a groupwhich is directly bonded to the ring through a carbon atom (for example,a lower alkyl group, a carboxyl group which may be protected, a1,3-benzodioxolyl group which may be substituted, a 1,4-benzodioxylgroup which may be substituted, a 1,3-benzodioxolylalkyl group which maybe substituted and a 1,4-benzodioxylalkyl group which may besubstituted); and R⁶ is a group selected from among those defined abovewith respect to NR⁷YR⁸ except a hydrogen atom, halogen atoms and loweralkyl groups in the general formula (I), a compound similar the generalformula (I) can be prepared by the following process:

[0062] [in a series of formulas R¹, R², R³ and R⁴, are each as definedabove; R⁵ _(b) represents a group selected from among a hydrogen atom, ahalogen atom, a group represented by the formula

[0063] (wherein R⁸ and m are each as defined above), a group representedby the formula —O—R⁹ (wherein R⁹ is as defined above), a heteroarylgroup which may be substituted and a group which is directly bonded tothe ring through a carbon atom (for example, a lower alkyl group, acarboxyl group which may be protected, a 1,3-benzodioxolyl group whichmay be substituted, a 1,4-benzodioxyl group which may be substituted, a1,3-benzodioxylalkyl group which may be substituted and1,4-benzodioxylalkyl group which may be substituted); R⁶ _(a) representsa group selected from among those defined above with respect to R⁶except a hydrogen atom, halogen atoms and lower alkyl groups; and Erepresents an eliminable group].

[0064] That is, this process is one for preparing an objective compound(V) by condensing a quinazoline derivative represented by the generalformula (IV) with a compound represented by the general formula (VI).

[0065] The eliminable group represented by E in the formula includeshalogen atoms and alkoxy groups.

[0066] This process may be conducted in the presence of a base at need.

[0067] The base includes organic bases such as triethylamine, pyridineand diisopropylethylamine; inorganic bases such as sodium carbonate,potassium carbonate, sodium hydrogencarbonate, sodium hydroxide andsodium hydride; and alkoxides such as sodium methoxide and potassiumt-butoxide.

[0068] As the reaction solvent, every solvent which is inert to thereaction can be used and examples thereof include ethanol, isopropylalcohol, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide. Thisprocess can be conducted even in the absence of any solvent in somecases.

[0069] The reaction temperature preferably ranges from −20 to 300° C.

Preparation Process 3

[0070] When R⁵ is a group selected from among those defined above withrespect to NR⁵R⁶ except a hydrogen atom, halogen atoms and groups whichare directly bonded to the quinazoline skeleton through a carbon atom;and R⁶ is a group selected from among those defined above with respectto R⁶ except halogen atoms in the general formula (I), a compoundsimilar to the general formula (I) can be prepared by the followingprocess:

[0071] (in a series of formulas, R¹, R² ₁ R³ and R⁴ are each as definedabove; R⁵ _(c) is a group selected from among those defined above withrespect to R⁵ except a hydrogen atom, halogen atoms and groups which aredirectly bonded to the quinazoline skeleton through a carbon atom;

[0072] R⁶ _(b) is a group selected from among those defined above withrespect to R⁶, except halogen atoms; and

[0073] F represents an eliminable group).

[0074] That is, this process is one for preparing an objective compound(VIII) by condensing a compound represented by the general formula (VII)with a compound represented by the general formula (IX).

[0075] The eliminable group represented by F in the formula includes,for example, halogen atoms, alkylthio groups and so forth.

[0076] This process may be conducted in the presence of a base at need.

[0077] The base includes organic bases such as triethylamine, pyridineand diisopropylethylamine; inorganic bases such as sodium carbonate,potassium carbonate, sodium hydrogencarbonate, sodium hydroxide andsodium hydride; and alkoxides such as sodium methoxide and potassiumt-butoxide.

[0078] As the reaction solvent, every solvent which is inert to thereaction can be used and examples thereof include ethanol, isopropanol,tetrahydrofuran, dimethylformamide and dimethyl sulfoxide.

[0079] The reaction temperature preferably ranges from 0 to 300° C.

Preparation Process 4

[0080] When R⁵ is a group represented by the formula

[0081] (wherein R²⁴ is a hydrogen atom or a lower alkyl group in thegeneral formula (I), a compound similar to the general formula (I) canalso be prepared by the following process:

[0082] (in a series of formulas, R¹, R², R³ and R⁴ and R⁶ are each asdefined above; and R²⁴ and R²⁵, each of which may be the same ordifferent from each other, represent each a hydrogen atom or a loweralkyl group).

[0083] That is, this process is one for preparing an objective compound(XI) by reacting a compound represented by the general formula (X) withan ordinary reducing agent or an ordinary nucleophilic reagent, eitherdirectly or through the oxidation of an alcohol (XII).

[0084] The reducing agent includes lithium aluminum hydride, sodiumborohydride, diisobutylaluminum hydride and so forth.

[0085] The nucleophilic reagent includes lower alkyl metals such asmethyllithium, methylmagnesium bromide and so forth.

[0086] The oxidizing agent to be used when the reaction is conductedthrough the alcohol (XII) includes potassium bichromate/sulfuric acid,dimethyl sulfoxide/oxalyl chloride and so forth.

[0087] As the reaction solvent, every solvent which is inert to thereaction can be used.

[0088] The reaction temperature ranges from 0° C. to the refluxingtemperature of the solvent.

Preparation Process 5

[0089] When R⁵ is a group represented by the formula

[0090] (wherein R¹⁰ and R²⁴ are each as defined above) in the generalformula (I), a compound represented by the general formula (I) can alsobe prepared by the following process

[0091] (in a series of formulas, R¹, R², R³, R⁴, R⁶, R¹⁰ and R²⁴ areeach as defined above).

[0092] That is, this process is one for preparing a compound representedby the formula (XIII) by reacting a compound represented by the generalformula (XI) with hydroxyamine.

[0093] As the reaction solvent, every solvent which is inert to thereaction can be used.

[0094] The reaction temperature ranges from 0° C. to the refluxingtemperature of the solvent.

Preparation Process 6

[0095] When R⁵ is a group represented by the formula

[0096] (wherein R²⁴ is as defined above; R²⁶ represents a hydrogen atomor a lower alkyl group; and R²⁷ represents a hydrogen atom, a loweralkyl group, a carboxyl group which may be protected or a carboxyalkylgroup which may be protected) in the general formula (I), a compoundrepresented by the formula (I) can also be prepared by the followingprocess:

[0097] (in a series of formulas, R¹, R², R³, R⁴, R⁶, R²⁴, R²⁶ and R²⁷are each as defined above; and Ph represents a phenyl group).

[0098] That is, this process is one for preparing a compound representedby the general formula (XV) by reacting a compound represented by thegeneral formula (XIV) with a compound represented by the general formula(XVI) or the general formula (XVII) through the Wittig reaction.

[0099] As the reaction solvent, every solvent which is inert to thereaction can be used.

[0100] The reaction temperature ranges from 0° C. to the refluxingtemperature of the solvent.

Preparation process 7

[0101] When R⁵ is a group represented by the formula

[0102] (wherein R²⁴, R²⁶, and R²⁷ are each as defined above) in thegeneral formula (I), a compound represented by the formula (I) can alsobe prepared by the following process:

[0103] (in a series of formulas, R¹, R², R³, R⁴, R⁶, R²⁴, R²⁶ and R²⁷are each as defined above).

[0104] That is, this process is one for preparing an objective compound(XVIII) by reducing the compound represented by the general formula (XV)prepared in the Preparation process 6.

[0105] The reduction can be conducted by conventional means, forexample, catalytic reduction using palladium/carbon or platinumcatalyst.

[0106] As the reaction solvent, every solvent which is inert to thereaction is used.

Preparation Process 8

[0107] When R⁶ is a group represented by the formula

[0108] (wherein R¹⁹, R²⁰, R²¹ and r are each as defined above) in thegeneral formula (I), a compound represented by the general formula (I)can also be prepared by the following process:

[0109] (in a series of formulas, R¹, R², R³, R⁴, R⁵, R¹⁹, R²⁰, R²¹ and rare each as defined above).

[0110] That is, this process is one for preparing an objective compound(XX) by reducing a compound represented by the general formula (XIX).

[0111] The reduction is conducted by conventional means, e.g., catalyticreduction using palladium/carbon or platinum catalyst or reduction withiron or tin.

[0112] As the reaction solvent, every solvent which is inert to thereaction can be used.

Preparation Process 9

[0113] When R⁵ is a group represented by the formula —O—R⁹ (wherein R⁹is a carboxyl group which may be protected) in the general formula (I),a compound represented by the formula (I) can be prepared by thefollowing process:

[0114] The first step

[0115] (in a series of formulas, R¹, R², R³, R⁴ and R⁶ are each asdefined above; and m represented 0 or an integer of 1 to 2).

[0116] That is, this process is one for preparing a compound representedby the general formula (XXII) by oxidizing a compound represented by thegeneral formula (XXI) by conventional means.

[0117] As the oxidizing agent, everyone can be used so far as it isconventionally used and examples thereof include chromium (VI), dimethylsulfoxide and oxalyl chloride.

[0118] As the reaction solvent, every solvent which is inert to thereaction can be used.

[0119] The reaction temperature ranges from 0° C. to the refluxingtemperature of the solvent.

[0120] The second step

[0121] (in a series of formulas, R¹, R², R³, R⁴, R⁶ and m are each asdefined above; and R²⁸, R²⁹ and R³⁰, each of which may be the same ordifferent from one another, represent each a hydrogen atom or a loweralkyl group).

[0122] That is, this process is one for preparing a compound representedby the general formula (XXIV) by reacting the compound (XXII) preparedin the first step with the Wittig reagents (XXIII) or (XXIII)′.

[0123] As the reaction solvent, everyone which is inert to the reactioncan be used.

[0124] The reaction temperature ranges from 0° C. to the refluxingtemperature of the solvent.

[0125] The third step

[0126] (in a series of formulas, R¹, R², R³, R⁴, R⁶, R²⁹, R³⁰ and m areeach as defined above).

[0127] That is, this process is one for preparing the objective compound(XXV) by reducing the compound (XXIV) prepared in the second step.

[0128] The reduction may be conducted by conventional means, andexamples thereof include catalytic reduction using palladium/carbon orplatinum catalyst.

Preparation Process 10

[0129] When R⁶ is a group represented by the formula

[0130] (wherein R¹⁹, R²⁰, R²¹ and r are each as defined above; and R³¹represents an acyl group, a lower alkylsulfonyl group or a loweralkyloxycarbonyl group) in the general formula (I), a compoundrepresented by the general formula (I) can also be prepared by thefollowing process:

[0131] (in a series of formulas, R¹, R², R³, R⁴, R⁵ R¹⁹, R²⁰, R²¹ andR³¹, and r are each as defined above).

[0132] That is, this process is one for preparing an objective compound(XXVI) by subjecting the compound represented by the general formula(XX) prepared in the Preparative process 8 to the conventionalacylation, sulfonylation or alkoxycarbonylation in the presence of abase.

[0133] As the acylating agent, every acylating agent which isconventionally used, for example, activated derivatives of carboxylicacids such as acid chloride, acid anhydride and mixed acid anhydride;and condensing agents such as dicyclohexylcarbodiimide is used.

[0134] As the sulfonylating agent, every sulfonylating agent which isconventionally used can be used and examples thereof include a loweralkylsulfonyl chloride and a lower alkylsulfonic anhydride.

[0135] The alkoxycarbonylating agent includes every alkoxycarbonylatingagent which is conventionally used, for example, a loweralkyloxycarbonyl chloride and a lower alkyl pyrocarbonate.

[0136] At the base, every base can be used and examples thereof includeorganic bases such as pyridine and triethylamine; and inorganic basessuch as sodium carbonate, potassium carbonate, sodium hydroxide andsodium hydride.

Preparation Process 11

[0137] When a compound similar to formula (I) is desired, except having2 rings A and B, the ring A is selected from any of a benzene ring, apyridine ring and a cyclohexane ring, the ring B is selected from amonga pyridine ring, a pyrimidine ring and an imidazole ring, R⁵ representsa group selected from among those defined above with respect to R⁵except groups which are directly bonded to the ring portion through acarbon atom; and R⁶ represents a group selected from among those definedabove with respect to R⁵ except groups which are directly bonded to thering portion through a carbon atom in the general formula (I), thecompound represented by the general formula (I) can also be prepared bythe following process. The case in which the ring portion forms aquinazoline skeleton is shown below as the representative of the above:

[0138] The first step

[0139] (in a series of formulas, R¹, R², R³ and R⁴ are each as definedabove; R⁵ _(a) represents a group selected from among those definedabove with respect to R⁵ except groups which are directly bonded to thering portion through a carbon atom; and X represents a halogen atom).

[0140] That is, the first step is a condensation reaction according to aconventional process.

[0141] Alcohol solvents such as isopropyl alcohol, ether solvents suchas tetrahydrofuran and dimethylformamide are preferably used as thereaction solvent. However, every solvent which is inert to the reactioncan be used.

[0142] In the case where R⁵ _(a) is bonded to the ring portion through anitrogen atom, it is preferred that the reaction is proceeded by heatingunder reflux in the presence of a tertiary amine such as triethylaminewhile removing HCI generated. While in the case where R⁵ _(a) is bondedto the ring portion through an oxygen atom or a sulfur atom, it ispreferred that the reaction is proceeded by heating under reflux in thepresence of an alkali such as sodium hydroxide and sodium carbonate.

[0143] The second step

[0144] (in a series of formulas, R¹, R², R³, R⁴, R⁵ _(a) and X are eachas defined above: R⁶ _(a) represents a group selected from among thosedefined above with respect to R⁶ except groups which are directly bondedto the ring portion through a carbon atom).

[0145] The second step is a reaction wherein the compound (XXVIII)obtained in the first step is condensed with a compound represented bythe formula R⁶ _(a)—H according to a conventional process.

[0146] Alcohol solvents such as isopropyl alcohol, ether solvents suchas tetrahydrofuran and dimethylformamide are preferably used as thereaction solvent. However, every solvent which is inert to the reactioncan be used.

[0147] In the case where R⁶ _(a) is bonded to the ring portion through anitrogen atom, it is preferred that the reaction is proceeded by heatingunder reflux in the presence of an organic base such as triethylamine,pyridine and ethyldiisopropylamine, an inorganic base such as sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, sodium hydrideand sodium hydroxide or an alkoxide such as sodium methoxide andpotassium t-butoxide. While in the case where R⁶ _(a) is bonded to thering portion through an oxygen atom or a sulfur atom, it is preferredthat the reaction is proceeded by heating under reflux in the presenceof an alkali such as sodium hydroxide and sodium carbonate.

Preparation Process 12

[0148] When the compound represented by the general formula (1) is acompound represented by the following general formula (XXXII):

[0149] the compound can also be prepared by the following process.

[0150] (in a series of formulas R¹, R², R³, R⁴, and R⁵ are each asdefined above; and R⁶ _(b) represents a group selected from among groupswhich are directly bonded to the ring portion through a carbon atom inthose defined above with respect to R⁶) .

[0151] That is, this process is one for preparing an objective compoundby reacting, for example, piperonyl chloride (XXXI) with a benzimidazolederivative represented by the general formula (XXX) in the presence ofan alkali by a conventional process.

[0152] Sodium iodide is preferred as alkali.

[0153] Although every solvent which is inert to the reaction can be usedas the reaction solvent, polar solvents such as dimethylforamide can becited as preferable ones.

[0154] The reaction temperature is preferably about 60 to 100° C.,particularly preferably about 70 to 80° C.

Preparation Process 13

[0155] Additional compounds can also be prepared by the followingprocess:

[0156] The first step

[0157] (in a series of formulas, R¹, R², R³ and R⁴ are each as definedabove; R⁶ _(d) represents a group selected from among those definedabove with respect to R⁶ except groups which are directly bonded to thering portion through a carbon atom; and Q and Q′ represent halogenatoms).

[0158] The first step is a condensation reaction according to aconventional process.

[0159] In the case where R⁶ _(d) is bonded to the ring portion through anitrogen atom, it is preferred that the reaction is proceeded by heatingunder reflux in the presence of an organic base such as triethylamine,pyridine and duisopropylethylamine, an inorganic base such as sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, sodiumhydroxide and sodium hydride or an alkoxide such as sodium methoxide andpotassium t-butoxide. While in the case where R⁶ _(d) is bonded to thering portion through an oxygen atom or a sulfur atom, it is preferredthat the reaction is proceeded by heating under reflux in the presenceof an inorganic base such as sodium hydroxide and sodium carbonate.

[0160] Every solvent which is inert to the reaction can be used as thereaction solvent, and examples thereof include alcohol solvents such asethanol and isopropyl alcohol, ether solvents such as tetrahydrofuran,dimethylformamide and dimethylsulfoxide. Further, in the presentprocess, the reaction can be proceeded in the absence of a reactionsolvent in some cases.

[0161] The second step

[0162] (in a series of formulas, R¹, R², R³, R⁴ R⁶ _(d) and Q are eachas defined above; and R⁵ _(d) represents a group selected from amongthose defined above with respect to R⁵ except groups which are directlybonded to the ring portion through a carbon atom).

[0163] That is, the second step is a process for preparing an objectivecompound in which the compound obtained in the first step is condensedwith a compound represented by the general formula R⁵ _(d)—H.

[0164] In the present process, the reaction can be processed in thepresence of a base at need.

[0165] As the base, organic bases such as triethylamine, pyridine anddiisopropylethylamine, inorganic bases such as sodium carbonate,potassium carbonate, sodium hydrogencarbonate, sodium hydroxide andsodium hydride and alkoxides such as sodium methoxide and potassiumt-butoxide can be cited.

[0166] Every solvent which inert to the reaction can be used as thereaction solvent, and examples thereof include alcohol solvents such asethanol and isopropanol, ether solvents such as tetrahydrofuran,dimethylformamide and dimethylsulfoxide.

[0167] The reaction temperature is preferably 0° C. to 300° C.

[0168] In the case where R⁵ _(d) is a group which is bonded to the ringportion through a nitrogen atom, it is preferred that the reaction isproceeded by heating under reflux in the presence of a tertiary aminesuch as triethylamine. While in the case where R⁵ _(d) is a group whichis bonded to the ring portion through a oxygen atom or a sulfur atom, itis preferred that the reaction is proceeded by heating under reflux inthe presence of an alkali such as sodium hydroxide and sodium carbonate.

[0169] The compounds thus obtained in the preparation processes 1 to 13described above can form salts thereof by a conventional process, forexample, by adding sodium hydroxide, potassium hydroxide ormethanesulfonic chloride.

[0170] Next, the preparation processes for the raw compounds used in thepreparation processes will be shown.

Preparation Process A

[0171] Among the starting materials used in the preparation process 13,the compound in which the ring portion is a quinazoline ring and Q andQ′ are chlorine atoms can also be prepared by the following process:

[0172] (in a series of formulas, R¹, R², R³ and R⁴ are each as definedabove; and X′ represents any group among a hydroxyl group, an alkoxygroup and an amino group).

[0173] That is, this process is one for preparing the objective compound(c) by cyclizing the compound (a) by a conventional process to obtainthe compound (b) and then chlorinating it by a conventional process.

[0174] The first step is a cyclization reaction. It is a step in whichurea is reacted with the compound (a) to obtain the compound (b). Inthis case, the reaction temperature is preferably about 170 to 190° C.,and although every solvent can be used as long as it is inert to thereaction, preferable examples thereof include N-methylpyrrolidone andthe like. In this step, the reaction can also be proceeded in theabsence of the solvent.

[0175] Further, the compound (b) can also be obtained by cyclizing withcarbonyldiimidazole or by cyclizing under an acidic or basic conditionafter converting to urethane with a chloroformic ester when X′ is anamino group.

[0176] The second step is a chlorination reaction. This step can becarried out by a conventional manner, and examples thereof include aprocess in which the compound (b) is heated under reflux with phosphoruspentachloride and phosphorus oxychloride, or phosphorus oxychloridewhile stirring to chlorinate.

Preparation Process B

[0177] The starting material (II) used in the preparation process 1 canbe prepared by the following process:

[0178] (in a series of formulas, R¹, R², R³ and R⁴ are each as definedabove; and R⁵ _(c) represents a halogen atom or a group selected fromamong groups which are directly bonded to the ring portion through acarbon atom in those defined with respect to above R⁵).

[0179] That is, the above process is a reaction in which an amideproduct is obtained by a conventional process in the first step and acyclization is carried out in the presence of an acid or a base in thesecond step.

[0180] The amide produce (e) can be obtained by a conventional process,and it can be obtained, for example, by reacting the compound (d) withan acylating agent such as an acid chloride represented by R⁵ _(c)—COCIin the presence of a base.

[0181] Tertiary amines such as triethylamine and organic bases such aspyridine are preferably cited as the base.

[0182] Specific examples of the acylating agent include acid chloridessuch as benzoyl chloride, acetyl chloride, ethyloxalyl chloride andbenzyloxyacetyl chloride.

[0183] The reaction temperature is preferably about 0° C. to 30° C.

[0184] In the second step, the compound (e) obtained in the first stepis heated under reflux in the presence of an acid or a base to obtainthe compound (f).

[0185] The acid includes acetic anhydride and the like.

[0186] The base includes sodium hydroxide and the like.

Preparation Process C

[0187] The starting material (II) can also be prepared by the followingprocess when R⁵ _(a) is a hydrogen atom in the preparation process 1:

[0188] (in a series of formulas, R¹, R², R³ and R⁴ are each as definedabove; and X″ represents a hydroxyl group or a lower alkoxy group).

[0189] That is, the above process is a cyclization reaction by aconventional process.

[0190] The objective compound (h) can be synthesized, for example, bycondensing the raw compound (g) with formamide by heating under reflux,or by heating it together with formic acid.

[0191] Examples of the present invention will now be described, thoughit is needless to say that the present invention is not limited to them.In advance of Examples, preparative examples of the raw compound forcompounds according to the present invention will be described. In theExamples, Me represents a methyl group, Et an ethyl group, Bzl a benzylgroup and Ac an acetyl group.

EXAMPLES Preparative Example 12-Ethoxycarbonyl-6-chloroquinazolin-4(3H)-one

[0192]

[0193] 2.50 g (0.0147 mol) of 2-amino-5-chlorobenzamide was dissolved in15 ml of pyridine. 2.0 ml of ethyloxalyl chloride was dropped into theobtained solution under stirring at room temperature. The obtainedmixture was stirred for several hours and distilled under a reducedpressure to remove the solvent. The obtained residue was used as such inthe subsequent reaction.

[0194] The residue was dissolved in 50 ml of acetic acid, followed bythe addition of 5 ml of acetic anhydride. The obtained mixture washeated under reflux for 24 hours. The solvent was distilled away under areduced pressure and ethanol was added to the obtained crystallineresidue. The obtained mixture was filtered to recover the crystal. Thecrystal was washed with ethanol and ether and air-dried to give 2.78 gof the title compound as a pale-yellow crystal.

[0195] yield (i); 75

[0196] m.p. (° C.); 239˜240

[0197] Mass; 253 (M+H)⁺

[0198] NMR δ (DMSO-d₆);

[0199] 1.36 (3H, t, J=7.2 Hz), 4.39 (2H, q, J=7.2 Hz), 7.86 (1H, d,J=8.8 Hz), 7.92 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.11(1H,d,J=2.4 Hz),12.85(1H,brs)

Example 12-Morpholino-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0200]

[0201] A mixture comprising 338 mg of2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline, 435 mg ofmorpholine and 20 ml of isopropyl alcohol was heated under reflux for 3hours, followed by the addition of 30 ml of water under heating. Theprecipitate thus formed was recovered by filtration and washed with 30ml of water and 30 ml of ethyl acetate. Thus, 310 mg of the titlecompound was obtained.

[0202] molecular formula; C₂₁H₁₉N₅O₃ (389)

[0203] yield (%); 80

[0204] m.p. (° C.); 270˜272 (dec.)

[0205] Mass; 390 (M+1)⁺

[0206] NMR δ (DMSO-d₆)

[0207] 3.57-3.61 (4H, m), 3.73˜3.79 (4H, m), 4.57 (2H, d, J=5.6 Hz),5.95 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.93 (1H,s), 7.27 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.56 (1H,d, J=1.6 Hz), 8.75 (1H, brt, J=5.6 Hz)

Examples 2 to 3

[0208] The following compounds were prepared in a similar manner to thatof Example 1.

Example 22-Morpholino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0209]

[0210] molecular formula; C₂₀H₁₉N₄O₃Cl (398.850)

[0211] yield (%); 96

[0212] m.p. (° C.); 208˜209

[0213] Mass; 399 (MH)⁺

[0214] NMR δ (DMSO-d₆);

[0215] 3.61 (4H, t, J=5 Hz), 3.72 (4H, t, J=5 Hz), 4.58 (2H, d, J=5.7Hz), 5.97 (2H, s), 6.85 (2H, s), 6.95 (1H, s), 7.28 (1H, d, J=9.0 Hz),7.51 (1H, dd, J=2.4 Hz, 9.0 Hz), 8.18 (1H, d, J=2.4 Hz), 8.60 (1H, t,J=5.7 Hz)

Example 32-Morpholino-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline

[0216]

[0217] molecular formula; C₂₁H₂₀N₅O₂Cl (407.5)

[0218] yield (%); 51

[0219] m.p. (° C.) ; 222˜223

[0220] Mass; 410 (M+1)⁺

[0221] NMR δ (DMSO-d₆);

[0222] 3.56˜3.61 (4H, m), 3.74˜3.80 (4H, m), 3.80 (3H, s), 4.58 (2H, d,J=5.2 Hz), 7.27˜7.32 (2H, m), 7.44 (1H, d, J=1.6 Hz), 7.75 (1H, dd,J=8.8 Hz, 1.6 Hz), 8.55 (1H, d, J=1.6 Hz), 8.80 (1H, brt, J=5.2 Hz)

Example 42-(4-Hydroxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-cyanoquinazoline

[0223]

[0224] A mixture comprising 339 mg of2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline, 500 mg of4-hydroxypiperidine and 20 ml of N,N-dimethyl-formamide was heated underreflux for 5 hours and poured into 50 ml of water, followed by theaddition of 50 ml of ethyl acetate. The obtained mixture was filtered toremove insolubles. The organic layer of the filtrate was dried overmagnesium sulfate and concentrated under a reduced pressure to give acrystalline residue. This residue was washed with chloroform to give 145mg of the title compound.

[0225] molecular formula; C₂₂H₂₁N₅O₃ (403)

[0226] yield (%); 36

[0227] m.p.(° C.); 229

[0228] Mass; 404 (M+1)⁺

[0229] NMR δ (DMSO-d₆);

[0230] 1.19˜1.30 (2H, m), 1.64˜1.77 (2H, m), 3.21˜3.30 (2H, m),3.63˜3.75 (1H, m), 4.34˜4.38 (2H, m), 4.55 (2H, d, J=5.6 Hz), 4.66 (1H,d, J=4.0 Hz), 5.94 (2H, s), 6.80˜6.86 (2H, m), 6.93 (1H, d, J=0.8 Hz),7.24 (1H, d, J=8.4 Hz), 7.70 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.52 (1H, d,J=1.6 Hz), 8.70 (1H, br)

Examples 5 to 11

[0231] The following compounds were prepared in a similar manner to thatof Example 4.

Example 52-(4-Hydroxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline

[0232]

[0233] molecular formula; C₂₁H₂₁N₄O₃Cl (412.877)

[0234] yield (%); 56

[0235] m.p. (° C.) ; 157˜158

[0236] Mass; 413 (MH⁺)

[0237] NMR δ (DMSO-d₆);

[0238] 1.2˜1.3 (2H, m), 1.6˜1.8 (2H, m), 3.1˜3.2 (2H, m), 3.6˜3.7 (1H,m), 4.3˜4.4 (2H, m), 4.55 (2H, d, J=5.7 Hz), 4.65 (1H, d, J=4.4 Hz),5.96 (2H, s), 6.84 (2H, s), 6.95 (1H, s), 7.24 (1H, d, J=9.0 Hz), 7.47(1H, dd, J=2.4 Hz, 9.0 Hz), 8.13 (1H, d, J=2.4 Hz), 8.53 (1H, t, J=5.7Hz)

Example 62-(4-Hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)-amino-6-cyanoquinazoline

[0239]

[0240] molecular formula; C₂₂H₂₂N₅O₂Cl (423.5)

[0241] yield (%); 80

[0242] m.p. (° C.); 207˜208

[0243] Mass; 424 (M+1)⁺

[0244] NMR δ (DMSO -d₆);

[0245] 1.18˜1.30 (2H, m), 1.65˜1.76 (2H, m), 3.21˜3.33 (2H, m), 3.30(3H, s), 3.64˜3.72 (1H, m), 4.29˜4.37 (2H, m), 4.57 (2H, d, J=5.6 Hz),4.66 (1H, d, J=1.8 Hz), 7.07 (1H, d, J=8.4 Hz), 7.24 (1H, d, J=8.8 Hz),7.29 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.43 (1H, d, J=2.0 Hz), 7.71 (1H, dd,J=8.8 Hz, 2.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.74 (1H, brt, J=1.8 Hz)

Example 7 2- (2-Hydroxyethyl)amino-4- (3,4-methylenedioxybenzyl)-amino-6,7,8- trimethoxyquinazoline

[0246]

[0247] molecular formula; C₂₁H₂₄N₄O₆

[0248] yield (%); 38

[0249] m.p.(° C.); amorphous

[0250] Mass; 429 (M+H)⁺

[0251] NMR δ (CDCl₃);

[0252] 3.60 (2H, m), 3.88 (3H, s&1H, m) , 3.99 (3H, s), 4.01 (3H, s),4.67 (2H, d, J=5.6 Hz), 5.32 (1H, brs), 5.53 (1H, brs), 5.97 (2H, s),6.55 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.89 (1H,s)

Example 8 2-(2-Hydroxyethyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline

[0253]

[0254] molecular formula; C₁₈H₁₇N₄O₃Cl

[0255] yield (%); 47

[0256] m.p.(° C.); 138˜139

[0257] Mass m/e; 373 (M+1)

[0258] NMR δ (CDCl₃(+DMSO-d₆));

[0259] 3.60 (2H, m), 3.79 (2H, t, J=4.8 Hz), 4.65 (2H, d, J=5.2 Hz),5.94 (2H, s), 6.76 (1H, d, J=8.0 Hz), 6.85 (1H, dd, J=8.0 Hz, 2.0 Hz),6.90 (1H, d, J=2.0 Hz), 7.34 (1H, d, J=8.8 Hz), 7.44 (1H, dd, J=8.8 Hz,2.4 Hz), 8.02 (2H, brs)

Example 92-[N-(2-Hydroxyethyl)-N-methylaminol-4-(3,4-methylene-dioxybenzyl)amino-6-chloroquinazoline

[0260]

[0261] molecular formula; C₁₉H₁₉N₄O₃Cl

[0262] yield (%); 48

[0263] m.p. (° C.); 146˜148

[0264] Mass m/e; 387 (M+1)

[0265] NMR δ (CDCl₃(+DMSO-d₆));

[0266] 3.27 (3H, s), 3.82 (2H, t, J=4.8 Hz) 3.89 (2H, t, J=4.8 Hz), 4.67(2H, d, J=5.6 Hz), 5.95 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.86 (1H, dd,J=8.0 Hz, 1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 7.43 (2H, m), 7.76 (1H, brs)

Example 102-(2-Hydroxymethylpyrrolidin-1-yl)-4-(3,4-methylene-dioxybenzyl)amino-6-chloroquinazoline

[0267]

[0268] molecular formula; C₂₁H₂₁N₄O₃Cl (412.877)

[0269] yield (%); 70

[0270] m.p. (° C.); 182˜183

[0271] Mass; 413 (MH⁺)

[0272] NMR δ (DMSO-d₆);

[0273] 1.8˜2.0 (4H, br 2 peaks), 3.4˜3.7 (3H, br 2 peaks), 4.1˜4.2 (1H,brs), 4.58 (2H, d, J=5.8 Hz), 5.96 (2H, s), 6.84 (1H, d, J=8.0 Hz), 6.88(1H, dd, J=1.3 Hz, 8.0 Hz), 6.96 (1H, d, J=1.3 Hz), 7.23 (1H, d, J=8.8Hz), 7.47 (1H, dd, J=2.4 Hz, 8.8 Hz), 8.15 (1H, d, J=2.4 Hz), 8.4˜8.6(1H, brs)

Example 11 2-Bis(2-hydroxyethyl)amino-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazoline

[0274]

[0275] molecular formula; C₂₀H₂₁N₄O₄Cl (416.865)

[0276] yield (%); 56

[0277] m.p. (° C.) ; 167˜168

[0278] Mass; 417 (MH⁺)

[0279] NMR δ (DMSO-d₆);

[0280] 3.5˜3.7 (8H, br 2 peaks), 4.56 (2H, d, J=5.7 Hz), 5.96 (2H, s),6.85 (2H, s), 6.93 (1H, s), 7.22 (1H, d, J=9.0 Hz), 7.47 (1H, dd, J=2.4Hz, 9.0 Hz), 8.15 (1H, d, J=2.4 Hz), 8.55 (1H, brt, J=5.7 Hz)

Example 122-(1-Imidazolyl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0281]

[0282] 103 mg of imidazole was added to a suspension of 66 mg of sodiumhydride in 6 ml of dimethylformamide at 0° C. The obtained mixture wasstirred for 10 minutes. 500 mg of2,6-dichloro-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline wasadded to the resulting mixture at room temperature. The mixture thusprepared was stirred at 100° C. for 20 minutes, followed by the additionof water. The crystals precipitated were recovered by filtration andwashed with water and ethanol/acetone successively to give 325 mg of thetitle compound.

[0283] molecular formula; C₁₉H₁₄N₅O₂Cl

[0284] yield (%); 59

[0285] m.p.(° C.); 275˜276 (dec.)

[0286] Mass m/e; 380 (M+1)

[0287] NMR δ (DMSO-d₆);

[0288] 4.74 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.85 (1H, d, J=8.0 Hz),6.95 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.03 (1H, d, J=1.6 Hz), 7.08 (1H, d,J=1.2 Hz), 7.68 (1H, d, J=8.8 Hz), 7.78 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.94(1H, d, J=1.2 Hz), 8.47 (1H, d, J=2.4 Hz), 8.58 (1H, t, J=2.4 Hz), 9.28(1H, t, J=5.6 Hz)

Examples 13 to 17

[0289] The following compounds were prepared in a similar manner to thatof Example 12.

Example 132-(Imidazol-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0290]

[0291] molecular formula; C₂₀H₁₄N₆O₂ (370)

[0292] yield (%); 81

[0293] m.p. (° C.) ; >290

[0294] Mass; 371 (M+1)⁺

[0295] NMR δ (DMSO-d₆);

[0296] 4.74 (2H, d, J=6.0 Hz), 5.95 (2H, s), 6.86 (1H, d, J=8.0 Hz),6.95 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.04 (1H, d, J=1.6 Hz), 7.09 (1H, d,J=1.6 Hz), 7.73 (1H, d, J=8.4 Hz), 7.95 (1H, d, J=1.6 Hz), 8.06 (1H, dd,J=8.4 Hz, 1.6 Hz), 8.61 (1H, d, J=1.6 Hz), 8.87 (1H, d, J=1.6 Hz), 9.47(1H, brt, J=6.0 Hz)

Example 142-Pentylamino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0297]

[0298] molecular formula; C₂₁H₂₃N₄O₂Cl

[0299] yield (%); 97

[0300] m.p. (° C.) ; 194˜195

[0301] Mass m/e; 399 (M+1)

[0302] NMR δ (CDCl₃);

[0303] 0.86 (3H, t, J=7.2 Hz), 1.29 (4H, m), 1.58 (2H, quintet, J=6.8Hz), 3.47 (2H, q, J=6.8 Hz), 4.78 (2H, d, J=5.6 Hz), 5.87 (2H, s), 6.66(1H, d, J=8.0 Hz), 6.89 (1H, d, J=8.0 Hz), 6.94 (1H, s), 7.26 (1H, d,J=8.8 Hz), 7.41 (1H, d, J=8.8 Hz), 7.90 (1H, t, J=5.6 Hz), 8.55 (1H, s),9.53 (1H, brs)

Example 152-(2-Aminoethyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6,7,8-trimethoxyquinazoline

[0304]

[0305] molecular formula; C₂₁H₂₅N₅O₅

[0306] yield (%); 87

[0307] m.p. (° C.); amorphous

[0308] Mass; 428 (M+H)⁺

[0309] NMR δ (CDCl₃);

[0310] 1.44 (2H, s), 2.93 (2H, t, J=6.0 Hz), 3.57 (2H, brs), 3.88 (3H,s), 4.00 (3H, s), 4.07 (3H, s), 4.70 (2H, d, J=4.8 Hz), 5.16 (1H, brs),5.51 (1H, brs), 5.96 (2H, s), 6.56 (1H, s), 6.80 (1H, d, J=8.0 Hz), 6.86(1H, d, J=8.0 Hz), 6.90 (1H, s)

Example 162-Hydrazino-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline

[0311]

[0312] molecular formula; C₁₉H₂₁N₅O₅

[0313] yield (%); 12

[0314] m.p. (° C.); oily substance

[0315] Mass; 400 (M+H)⁺

[0316] NMR δ (CDCl₃);

[0317] 3.88 (3H, s), 3.99 (3H, s), 4.05 (3H, s), 4.66 (2H, d, J=3.6 Hz),5.92 (2H, s), 6.75 (1H, d, J=8.0 Hz), 6.83 (1H, d, J=8.0 Hz), 6.87 (1H,s), 7.04 (2H, brs)

Examale 172-(Carbamoylmethyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline

[0318]

[0319] molecular formula; C₁₈H₁₆N₅O₃Cl

[0320] yield (%); 63

[0321] m.p. (° C.); 259˜260 (dec.)

[0322] Mass m/e; 386 (M+1)

[0323] NMR δ (DMSO-d₆);

[0324] 4.02 (2H, d, J=4.8 Hz), 4.66 (2H, d, J=5.6 Hz), 5.97 (2H, s),6.86 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 6.99 (1H, s), 7.19 (1H,s), 7.50 (1H, d, J=8.8 Hz), 7.61 (1H, S), 7.83 (1H, d, J=8.8 Hz), 8.09(1H, brs), 8.49 (1H, brs), 10.03 (1H, brs)

Example 182-(3,4-Methylenedioxybenzyl)amino-4,6,7,8-tetramethoxy-quinazoline

[0325]

[0326] 1.00 g (3.51 mmol) of 2-chloro-4,6,7,8-tetra-methoxyquinazoline,0.60 g (3.97 mmol) of piperonyl-amine and 0.60 g of sodium carbonatewere mixed with 30 ml of isopropyl alcohol. The obtained mixture washeated under reflux for 24 hours and distilled under a reduced pressureto remove the solvent. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane) to give 0.12 g of the titlecompound as an oily substance.

[0327] molecular formula; C₂₀H₂₁N₃O₆

[0328] yield (%); 9

[0329] m.p. (° C.); oily substance

[0330] NMR δ (CDCl₃) ;

[0331] 3.91 (3H, s), 4.02 (3H, s), 4.04 (6H, s), 4.63 (2H, d, J=6.0 Hz),5.30 (1H, brs), 5.93 (2H, s), 6.75 (1H, d, J=8.0 Hz), 6.86 (1H, dd,J=8.0 Hz, 1.6 Hz), 6.92 (1H, d, J=1.6 Hz), 7.06 (1H, s)

Example 19 2-Chloro-4,6,7,8-tetramethoxyquinazoline

[0332]

[0333] 5.00 g (17.3 mmol) of 2,4-dichloro-6,7,8-trimethoxyquinazolinewas suspended in 100 ml of methanol, followed by the gradual addition of1.5 g of sodium hydride. The obtained mixture was heated under reflux.After several hours, the reaction mixture was concentrated under areduced pressure, followed by the addition of water. The crystal thusprecipitated was recovered by filtration, washed with water andair-dried to give 4.80 g of the title compound as a pale-pink crystal.

[0334] yield (%); 97

[0335] m.p. (° C.); 119˜120

[0336] Mass; 285 (M+1)⁺

[0337] NMR δ (CDCl₃);

[0338] 3.98 (3H, s), 4.06 (3H, s), 4.12 (3H, s), 4.19 (3H, s), 7.17 (1H,s)

Example 20 2-Amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0339]

[0340] 2.0 g of2.6-dichloro-4-(3,4-methylenedioxy-benzyl)aminoquinazoline was heated to120° C. in 50 ml of ethanolic ammonia put in a pressure vessel for 18hours, cooled and concentrated under a reduced pressure. The obtainedresidue was introduced to a silica gel column and eluted with achloroform/methanol (9:1) mixture to give 830 mg of the title compound.

[0341] molecular formula; C₁₆H₁₃N₄O₂Cl

[0342] yield (%); 44

[0343] m.p. (° C.); 285 (dec.)

[0344] Mass; 329 (M+1)⁺

[0345] NMR δ (CDCl₃);

[0346] 4.67 (2H, d, J=5.6 Hz), 4.98 (2H, br), 5.74 (1H, br), 5.96 (2H,s), 6.78 (1H, d, J=7.6 Hz), 6.83 (1H, dd, J=7.6 Hz, 1.6 Hz), 6.86 (1H,d, J=1.6 Hz), 7.38 (1H, d, J=9.6 Hz), 7.46˜7.49 (2H, m)

Example 21 2-Amino-4-(3,4-methylenedioxybenzyl)amino-6-cyano-quinazoline

[0347] The title compound was prepared in a similar manner to those ofExamples 19 and 20.

[0348] molecular formula; C₁₇H₁₃N₅O₂ (319)

[0349] yield (%); 60

[0350] m.p. (° C.); 284 (dec.)

[0351] Mass; 320 (M+1)⁺

[0352] NMR δ (CDCl₃);

[0353] 4.31 (2H, d, J=5.6 Hz), 5.25 (2H, brs), 5.58 (2H, s), 6.40 (1H,d, J=7.6 Hz), 6.51 (1H, dd, J=7.6 Hz, 1.2 Hz), 6.57 (1H, d, J=1.2 Hz),6.95 (1H, d, J=8.4 Hz), 7.25 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.00 (1H, br),8.20 (1H, d, J=1.6 Hz)

Example 222-(Methylcarbamoyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline

[0354]

[0355] 4 ml of dimethyl sulfoxide and 260 mg of methyl isocyanate wereadded to 500 mg of2-amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. Theobtained mixture was stirred at 50° C. for 3 hours and distilled under areduced pressure to remove excess methyl isocyanate, followed by theaddition of chloroform and water. The mixture thus obtained was filteredand the filtrate was extracted with chloroform twice. The organic layerswere combined, washed with water twice, dried over magnesium sulfate anddistilled under a reduced pressure to remove the solvent. The residuewas purified by silica gel column chromatography (benzene/acetone) andrecrystallized (from benzene/chloroform/ethanol) to give 72 mg of thetitle compound.

[0356] molecular formula; C₁₈H₁₆N₅O₃Cl

[0357] yield (%); 12

[0358] m.p. (° C.); 245˜247

[0359] Mass m/e; 386 (M+1)

[0360] NMR δ (DMSO-d₆);

[0361] 2.75 (3H, d, J=4.4 Hz), 4.56 (2H, d, J=6.0 Hz), 5.95 (2H, s),6.82 (1H, d, J=8.4 Hz), 6.92 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.56 (1H,d, J=8.8 Hz), 7.67 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.27 (1H, d, J=1.6 Hz),8.90 (1H, t, J=6.0 Hz), 9.20 (1H, s), 9.38 (1H, d, J=4.4 Hz)

Examples 23 and 24

[0362] The following compounds were prepared in a similar manner to thatof Example 22.

Example 232-Bis(methylcarbamoyl)amino-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazoline

[0363]

[0364] molecular formula; C₂₀H₁₉N₆O₄Cl

[0365] yield (%); 8

[0366] amt. of product (mg); 45

[0367] m.p. (° C.); 243˜245

[0368] Mass m/e; 443 (M+1)

[0369] NMR δ (DMSO-d₆);

[0370] 2.71 (6H, d, J=4.8 Hz), 4.53 (2H, d, J=6.0 Hz), 5.94 (2H, s),6.80 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.95 (1H, s), 7.66 (1H,d, J=8.8 Hz), 7.72 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.32 (1H, dd, J=2.0 Hz),8.85 (1H, dd, J=4.8 Hz), 9.01 (1H, t, J=6.0 Hz)

Example 242-(n-Butylcarbamoyl)amino-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline

[0371]

[0372] molecular formula; C₂₁H₂₂N₅O₃Cl

[0373] yield (%); 40

[0374] m.p. (° C.); 209˜210

[0375] Mass m/e; 428 (M+1)

[0376] NMR δ (DMSO-d₆);

[0377] 0.89 (3H, t, J=7.2 Hz), 1.33 (2H, sextet, J=7.2 Hz), 1.45 (2H,quintet, J=7.2 Hz), 3.18 (2H, t, J=7.2 Hz), 4.56 (2H, d, J=6.0 Hz), 5.95(2H, s), 6.83 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 7.09 (1H, s),7.46 (1H, d, J=8.8 Hz), 7.66 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.27 (1H, d,J=2.0 Hz), 8.90 (1H, t, J=6.0 Hz), 9.17 (1H, s), 9.58 (1H, t, J=7.2 Hz)

Example 252-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazoline

[0378]

[0379] 3.61 g of methyl isonipecotate, 2.32 g of triethylamine and 5 mlof 2-propanol were added to 1 g of2,6-dichloro-4-(3,4-methylenedioxybenzyl)amino-quinazoline prepared inExample 92. The obtained mixture was refluxed for 100 minutes. Themixture thus obtained was extracted with chloroform twice. The organiclayers were combined, washed with water, dried over magnesium sulfateand freed from the solvent by distillation. The residue wasrecrystallized (from ethanol/water) to give 1.31 g of the titlecompound.

[0380] molecular formula; C₂₄H₂₅ClN₄O₄

[0381] yield (%); 97

[0382] m.p. (° C.); 118˜119

[0383] Mass; 469 (M+1)

[0384] NMR δ (DMSO-d₆);

[0385] 1.18 (3H, t, J=7.2 Hz), 1.42 (2H, m), 2.58 (1H, m), 2.98 (2H, m),4.06 (2H, q, J=7.2 Hz), 4.56 (2H, m, J=5.6 Hz), 4.62 (2H, m), 5.96 (2H,s), 6.82 (1H, d, J=8.0 Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.94 (1H,d, J=1.6 Hz), 7.26 (1H, d, J=9.2 Hz), 7.48 (1H, dd, J=9.2 Hz, 2.4 Hz),8.15 (1H, d, J=2.4 Hz), 8.56 (1H, brt, J=5.6 Hz)

Example 262-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazolinehydrochloride

[0386]

[0387] The title compound was prepared from the2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazolineprepared in Example 205 by the use of ethanol-hydrochloric acid-ethanol.

[0388] molecular formula; C₂₄H₂₅ClN₄O₄.HCl

[0389] yield (%); 97

[0390] m.p. (° C.); 174˜175

[0391] NMR δ (DMSO-d₆);

[0392] 1.20 (3H, t, J=7.2 Hz), 1.59 (2H, m), 1.97 (2H, m), 2.75 (1H, m),3.31 (2H, m), 4.09 (2H, q, J=7.2 Hz), 4.53 (2H, m), 4.67 (2H, d, J=5.6Hz), 5.98 (2H, s), 6.86 (1H, d, J=8.0 Hz), 6.90 (1H, dd, J=8.0 Hz, 1.6Hz), 7.01 (1H, d, J=1.6 Hz), 7.83 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.91 (1H,d, J=8.8 Hz), 8.52 (1H, d, J=2.0 Hz), 10.15 (1H, brs), 12.28 (1H, brs)

Example 272-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-cyanoquinazoline

[0393]

[0394] 3.71 g of ethyl isonipecotate, 2.38 g of triethylamine and 10 mlof 2-propanol were added to 1 g of 2-chloro-4-(3,4-methylenedioxybenzyl) amino-6-cyanoquinazoline. The obtainedmixture was refluxed for 1 hour and cooled to room temperature. Thecrystals thus precipitated were recovered by filtration and washed withwater and ether successively to give 1.126 g of the title compound.

[0395] molecular formula; C₂₅H₂₅N₅O₄

[0396] yield (%); 83

[0397] m.p. (° C.); 192˜193

[0398] Mass; 460 (M+1)

[0399] NMR δ (CDCl₃);

[0400] 1.26 (3H, t, J=7.2 Hz), 1.71 (2H, m), 1.99 (2H, m), 2.59 (1H, m),3.12 (2H, brt, J=12.0 Hz), 4.15 (2H, q, J=7.2 Hz), 4.67 (2H, d, J=5.2Hz), 4.82 (2H, dt, J=13.2 Hz, 3.6 Hz), 5.96 (2H, s)r 6.79 (1H, d, J=8.0Hz), 6.85 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.88 (1H, d, J=1.6 Hz), 7.42 (1H,brs), 7.61 (1H, dd, J=8.8 Hz, 1.6 Hz), 7.84 (1H, brs)

Example 282-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6-cyanoquinazoline

[0401]

[0402] 3.5 g of ethyl isonipecotate, 2.25 g of triethylamine and 30 mlof 2-propanol were added to 1 g of2-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyano-quinazoline. Theobtained mixture was refluxed for 30 minutes and cooled to roomtemperature. The crystals thus precipitated were recovered by filtrationand washed with water and ethanol successively to give 1.13 g of thetitle compound.

[0403] molecular formula; C₂₅H₂₆N₅O₃Cl

[0404] yield (%); 85

[0405] m.p. (° C.) ; 202˜203

[0406] Mass; 480 (M+1)

[0407] NMR δ (CDCl₃);

[0408] 1.26 (3H, t, J=7.2 Hz), 1.72 (2H, m), 1.99 (2H, m), 2.59 (1H, m),3.13 (2H, brt, J=11.2 Hz), 3.90 (3H, s), 4.15 (2H, q, J=7.2 Hz), 4.69(2H, d, J=5.6 Hz), 4.80 (2H, m), 6.91 (1H, d, J=8.4 Hz), 7.25 (1H, dd,J=8.4 Hz, 2.4 Hz), 7.42 (1H, d, J=2.4 Hz), 7.43 (1H, brs), 7.61 (1H, dd,J=8.8 Hz, 1.6 Hz), 7.87 (1H, brs)

Example 292-[N-(3-Ethoxycarbonylpropyl)-N-methylaminol-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0409]

[0410] 858 mg of ethyl N-methyl-4-aminobutyrate hydrochloride, 238 mg oftriethylamine, 4 ml of 2-propanol and 2 ml of N,N-dimethylformamide wereadded to 400 mg of2-chloro-4-(3,4-methylenedioxybenzyl)-amino-6-cyanoquinazoline. Theobtained mixture was refluxed for 1 hour, cooled to room temperature andfiltered. The filtrate was distilled under a reduced pressure to removethe solvent and the residue was recrystallized (from ethanol/water) togive 410 mg of the title compound.

[0411] molecular formula; C₂₄H25N₅O₄

[0412] yield (%); 78

[0413] m.p. (° C.); 152˜153

[0414] Mass; 448 (M+1)

[0415] NMR δ (CDCl₃);

[0416] 1.22 (3H, t, J=6.8 Hz), 1.97 (2H, brs), 2.30 (2H, brs), 3.24 (3H,s), 3.75 (2H, brs), 4.10 (2H, q, J=6.8 Hz), 4.68 (2H, d, J=5.2 Hz), 5.96(2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.87 (1H, s),7.42 (1H, brs), 7.60 (1H, d, J=8.8 Hz), 7.81 (1H, brs)

Examples 30 to 41

[0417] The following compounds were prepared in a similar manner to thatof Examples 25 to 29.

Example 302-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6,7,8-trimethoxyquinazolinehydrochloride

[0418]

[0419] molecular formula; C₂₇H₃₂N₄O₇.HCl

[0420] yield (%); 65

[0421] m.p. (° C.) ; 148˜150

[0422] Mass; 525 (M+1)

[0423] NMR δ (CDCl₃);

[0424] 1.275 (3H, t, J=7.2 Hz), 1.76 (2H, m), 2.03 (2H, m), 2.63 (1H,m), 3.38 (2H, m), 3.99 (3H, s), 4.08 (3H, s), 4.12 (3H, s), 4.17 (2H, q,J=7.2 Hz), 4.28 (2H, m), 4.63 (2H, d, J=6.0 Hz), 5.88 (2H, s), 6.68 (1H,d, J=8.0 Hz), 6.92 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.97 (1H, d, J=1.6 Hz),8.23 (1H, s), 9.38 (1H, brs), 11.1 (1H, s)

Example 312-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6,7,8-trimethoxyquinazolinehydrochloride

[0425]

[0426] molecular formula; C₂₇H₃₃N₄O₆Cl.HCl

[0427] yield (%); 93

[0428] m.p.(° C.); 177˜178

[0429] Mass; 545 (M+1)

[0430] NMR δ (CDCl₃);

[0431] 1.27 (3H, t, J=7.2 Hz), 1.80 (2H, m), 2.06 (2H, m), 2.67 (1H, m),3.40 (2H, m), 3.82 (3H, s), 3.98 (3H, s), 4.07 (3H, s), 4.11 (3H, s),4.17 (2H, q, J=7.2 Hz), 4.27 (2H, m), 4.65 (2H, d, J=6.0 Hz), 6.84 (1H,d, J=8.8 Hz), 7.40 (1H, d, J=2.0 Hz), 7.48 (1H, dd, J=8.8 Hz, 2.0 Hz),8.23 (1H, s), 9.26 (1H, s), 11.27 (1H, brs)

Example 322-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6-chloroquinazolinehydrochloride

[0432]

[0433] molecular formula; C₂₄H₂₆N₄O₃Cl₂.HCl

[0434] yield (%); 97

[0435] m.p. (° C.) ; 201˜204

[0436] Mass; 489 (M+1)

[0437] NMR δ (DMSO-d₆);

[0438] 1.17 (3H, t, J=7.2 Hz),, 1.56 (2H, m) 1.93 (2H, m), 2.71 (1H, m),3.30 (2H, m), 3.80 (3H, s), 4.06 (2H, q, J=7.2 Hz), 4.48 (2H, m), 4.66(2H, d, J=5.2 Hz), 7.09 (1H, d, J=8.4 Hz), 7.34 (1H, dd, J=8.4 Hz, 2.0Hz), 7.49 (1H, d, J=2.0 Hz), 7.83 (2H, brs), 8.48 (1H, brs), 10.8 (1H,brs)

Example 332-(Ethoxycarbonylmethyl)amino-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazoline

[0439]

[0440] molecular formula; C₂₀H₁₉N₄O₄Cl

[0441] yield (%); 55

[0442] m.p.(° C.); 218˜219 (dec.)

[0443] Mass m/e; 415 (M+1)

[0444] NMR δ (DMSO-d₆) 1.13 (3H, t, J=7.2 Hz), 4.07 (2H, q, J=7.2 Hz),4.18 (2H, brs), 4.63 (2H, brd, J=4.0 Hz), 5.97 (2H, s), 6.85˜6.92 (3H,m), 7.53 (1H, brs), 7.84 (1H, brd, J=8.0 Hz), 8.35 (1H, brs), 8.50 (2H,m)

Example 34 2-(3-Ethoxycarbonylpropyl)amino-4-(3,4-methylenedioxy-benzyl)amino -6-chloroquinazoline

[0445]

[0446] molecular formula; C₂₂H₂₃N₄O₄Cl

[0447] yield (%); 44

[0448] m.p. (° C.); 96˜98

[0449] Mass m/e; 443 (M+1)

[0450] NMR δ (CDCl₃);

[0451] 1.24 (3H, t, J=6.8 Hz), 1.96 (2H, quintet, J=7.2 Hz), 2.41 (2H,t, J=7.2 Hz), 3.54 (2H, q, J=7.2 Hz), 4.12 (2H, q, J=6.8 Hz), 4.66 (2H,q, J=5.2 Hz), 5.97 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0Hz), 6.87 (1H, s), 7.30 (1H, d, J=8.0 Hz), 7.44 (1H, s), 7.47 (1H, d,J=8.0 Hz)

Example 352-[N-(3-Ethoxycarbonylpropyl)-N-methylaminol-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazolinehydrochloride

[0452]

[0453] molecular formula; C₂₃H₂₅N₄O₄Cl.HCl

[0454] yield (%); 67

[0455] m.p. (° C.); 182˜183

[0456] Mass; 457 (M+1)

[0457] NMR δ (CDCl₃+DMSO-d₆);

[0458] 1.23 (3H, t, J=7.2 Hz), 1.90 (2H, brs), 2.25 (2H, brs), 2.84 (3H,brs), 3.56 (2H, brs), 4.10 (2H, q, J=7.2 Hz), 4.70 (2H, d, J=5.6 Hz),5.94 (2H, s), 6.76 (1H, d, J=7.6 Hz), 6.87 (2H, m), 7.54 (1H, dd, J=9.2Hz, 2.0 Hz), 8.40 (1H, d, J=2.0 Hz), 8.66 (1H, d, J=9.2 Hz), 9.69 (1H,brs)

Example 362-(5-Ethoxycarbonylpentyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0459]

[0460] molecular formula; C₂₄H₂₇N₄O₄Cl

[0461] yield (%); 46

[0462] m.p. (° C.); 109˜110

[0463] Mass m/e; 471 (M+1)

[0464] NMR δ (CDCl₃) ;

[0465] 1.25 (3H, t, J=7.2 Hz), 1.43 (2H, quintet, J=7.6 Hz), 1.66 (4H,m), 2.31 (2H, t, J=7.6 Hz), 3.49 (2H, q, J=7.6 Hz), 4.12 (2H, q, J=7.2Hz), 4.68 (2H, d, J=5.2 Hz), 5.97 (2H, s), 6.79 (1H, d, J=8.0 Hz), 6.84(1H, d, J=8.0 Hz), 6.87 (1H, s), 7.43 (3H, m)

Example 37(S)-2-(N-2-Ethoxycarbonylpyrrolidin-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazolinehydrochloride

[0466]

[0467] molecular formula; C₂₃H₂₃N₄O₄Cl.HCl

[0468] yield (%) ; 52

[0469] m.p. (° C.) ; 206˜208

[0470] Mass; 455 (M+1)

[0471] NMR δ (CDCl₃) ;

[0472] 1.19 (3H, t, J=7.2 Hz), 2.17 (3H, m), 2.32 (1H, m), 4.12 (2H, m),4.24 (2H, m), 4.62 (2H, m), 4.67 (1H, m), 5.93 (2H, s) 6.77 (1H, d,J=8.0 Hz), 6.86 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.89 (1H, d, J=1.6 Hz), 7.54(1H, d, J=8.8 Hz), 8.38 (1H, s), 8.64 (1H, d, J=8.8 Hz), 9.67 (1H, brs),13.38 (1H, brs)

Example 482-(N-Ethoxycarbonylmethyl-N-methylamino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0473]

[0474] molecular formula; C₂₂H₂₁N₅O₄

[0475] yield (%); 75

[0476] m.p. (° C.); 171˜172

[0477] Mass; 420 (M+1)

[0478] NMR δ (DMSO-d₆);

[0479] 1.12 (3H, m), 3.18 (3H, s), 4.03 (2H, m), 4.38 (2H, m), 4.51 (2H,m), 5.95 (2H, s), 6.84 (3H, m), 7.30 (1H, m), 7.76 (1H, m), 8.58 (1H,s), 8.79 (1H, m)

Example 392-[N-Ethyl-N-(3-ethoxycarbonylpropyl)aminol-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0480]

[0481] molecular formula; C₂₅H₂₇N₅O₄ (461.522)

[0482] yield (%); 61

[0483] m.p. (° C.); 142˜143

[0484] Mass; 462 (M+1)

[0485] NMR δ (DMSO-d₆);

[0486] 1.0˜1.15 (3H, br 2 peaks), 1.13 (3H, t, J=7.1 Hz), 1.65˜1.9 (2H,br 2 peaks), 2.15˜2.35 (2H, br 2 peaks), 3.58 (4H, brs), 4.01 (2H, q,J=7.1 Hz), 4.58 (2H, d, J=5.7 Hz), 5.96 (2H, s), 6.84 (2H, s), 6.93 (1H,s), 7.25 (1H, brs), 7.72 (1H, dd, J=1.8 Hz, 8.8 Hz), 8.56 (1H, d, J=1.8Hz), 8.72 (1H, t, J=5.7 Hz)

Example 402-[N-(3-Ethoxycarbonylpropyl)-N-methylamino]-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline

[0487]

[0488] molecular formula; C₂₄H₂₆N₅O₃Cl

[0489] yield (%); 72

[0490] m.p. (° C.); 127˜128

[0491] Mass; 468 (M+1)

[0492] NMR δ (DMSO-d₆);

[0493] 1.11 (3H, t, J=7.2 Hz), 1.74 (2H, brs), 2.14 (2H, brs), 3.09 (3H,s), 3.62 (2H, brs), 3.81 (3H, s), 3.98 (2H, q, J=7.2 Hz), 4.61 (2H, d,J=6.0 Hz), 7.07 (1H, d, J=8.8 Hz), 7.20˜7.36 (2H, m), 7.42 (1H, s), 7.72(1H, d, J=8.8 Hz), 8.55 (1H, s), 8.75 (1H, t, J=6.0 Hz)

Example 41(S)-2-(N-2-Ethoxycarbonylpyrrolidin-1-yl)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazolinehydrochloride

[0494]

[0495] molecular formula; C₂₄H₂₃N₅O₄.HCl

[0496] yield (%); 44

[0497] m.p. (° C.); 231˜232

[0498] Mass; 446 (M+1)

[0499] NMR δ (CDCl₃) ;

[0500] 1.21 (3H, t, J=7.2 Hz), 2.19 (3H, m), 2.36 (1H, m), 4.15 (2H, m), 4.28 (2H, m), 4.62 (2H, m), 4.76 (1H, m), 5.95 (2H, s), 6.79 (1H, d,J=8.0 Hz) , 6.86 (1H, d, J=8.0 Hz), 6.88 (1H, s), 7.80 (1H, dd, J=8.8Hz, 1.6 Hz), 8.82 (1H, d, J=1.6 Hz), 8.87 (1H, d, J=8.8 Hz), 9.85 (1H,brs), 13.81 (1H, s)

Example 42 2- (4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0501]

[0502] 10 ml of ethanol, 5 ml of water and 820 mg of sodium hydroxidewere added to 1 g of2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline.The obtained mixture was refluxed for 20 minutes, concentrated under areduced pressure and neutralized with 1 N hydrochloric acid. Thecrystals thus precipitated were recovered by filtration to give 920 mgof the title compound.

[0503] molecular formula; C₂₂H₂₁N₄O₄Cl

[0504] yield (%); 98

[0505] m.p. (° C.); 221˜222

[0506] Mass m/e; 441 (M+1)

[0507] NMR δ (DMSO-d₆)

[0508] 1.38 (2H, m), 1.80 (2H, dd, J=13.2 Hz, 2.4 Hz), 2.48 (1H, m),2.96 (2H, t, J=12.0 Hz), 4.54 (2H, d, J=5.6 Hz), 4.56 (2H, dt, J=12.0Hz, 3.2 Hz), 5.94 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0Hz), 6.93 (1H, s), 7.24 (1H, d, J=9.2 Hz), 7.46 (1H, dd, J=9.2 Hz, 2.0Hz), 8.13 (1H, d, J=2.0 Hz), 8.55 (1H, t, J=5.6 Hz)

Example 43 Sodium2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0509]

[0510] 12 ml of a 1N aqueous solution of sodium hydroxide and 40 ml ofwater were added to 5.00 g (11.3 mmol) of the 2- (4-carboxypiperidino)-4- (3,4-methylenedioxybenzyl)amino-6- chloroquinazoline prepared inExample 222. The obtained mixture was dissolved by heating and cooled byallowing to stand. The crystals thus precipitated were recovered byfiltration under suction, washed with a small amount of water, andvacuum-dried in the presence of phosphorus pentaoxide to give 4.34 g ofthe title compound.

[0511] molecular formula; C₂₂H₂₀ClN₄O₄Na

[0512] yield (%); 98

[0513] NMR δ (DMSO-d₆);

[0514] 1.42(2H, m), 1.73(2H, m), 2.06 (1H, M), 2.95 (2H, M), 4.52 (2H,m), 4.56 (2H, d, J=5.6 Hz), 5.95 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.86(1H, dd, J=8.0 Hz, 1.6 Hz), 6.95 (1H, d, J=1.6 Hz), 7.22 (1H, d, J=9.2Hz), 7.44 (1H, dd, J=9.2 Hz, 2.4 Hz), 8.13 (1H, d, J=2.4 Hz), 8.58 (1H,brt, J=5.6 Hz)

Example 44 Potassium2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0515]

[0516] 12.5 ml of a 1N aqueous solution of potassium hydroxide and 40 mlof water were added to 5.50 g (12.5 mmol) of the 2-(4-carboxypiperidino) -4-(3,4-methylene-dioxybenzylamino)-6-chloroquinazoline prepared in Example222. The obtained mixture was dissolved by heating and filtered. Thefiltrate was concentrated in a vacuum. Ethanol and ether were added tothe obtained residue to precipitate crystals. The crystals wererecovered by filtration, washed with ether, and vacuum-dried in thepresence of phosphorus pentaoxide to give 4.69 g of the title compound.

[0517] molecular formula; C₂₂H₂₀ClN₄O₄K

[0518] yield (%); 78

[0519] m.p. (° C.); 230˜234 (dec.)

[0520] NMR δ (DMSO-d₆);

[0521] 1.39 (2H, m), 1.69 (2H, m), 1.96 (1H, m), 2.94 (2H, m), 4.48 (2H,m), 4.55 (2H, d, J=5.6 Hz), 5.96 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.86(1H, dd, J=8.0 Hz, 1.6 Hz), 6.94 (1H, d, J=1.6 Hz), 7.22 (1H, d, J=8.8Hz), 7.43 (1H, dd, J=8.8 Hz, 2.4 Hz), 8.11 (1H, d, J=2.4 Hz), 8.50 (1H,brt, J=5.6 Hz)

Example 452-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazolinehydrochloride

[0522]

[0523] 2.00 g (4.54 mmol) of the 2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline prepared in Example222 was dissolved in a mixture comprising 25 ml of tetrahydrofuran and25 ml of ethanol under heating, followed by the dropwise addition of 1.0ml of an 8M ethanolic solution of hydrochloric acid. The obtainedmixture was cooled by allowing to stand to precipitate crystals. Thecrystals were recovered by filtration, washed with tetrahydrofuran, andair-dried to give 1.87 g of the title compound.

[0524] molecular formula; C₂₂H₂₁N₄O₄Cl.HCl

[0525] yield (%) ; 86

[0526] m.p. (° C.); 284˜286

[0527] NMR δ (DMSO-d₆);

[0528] 1.58 (2H, m) , 1.96 (2H, m), 2.65 (1H, m), 3.3 (2H, m), 4.47 (2H,m), 4.67 (2H, d, J=5.6 Hz), 5.98 (2H, s), 6.87 (1H, d, J=8.0 Hz), 6.90(1H, dd, J=8.0 Hz, 1.6 Hz), 7.00 (1H, d, J=1.6 Hz), 7.83 (2H, brs), 8.49(1H, brs), 10.09 (1H, brs), 12.11 (1H, brs), 12.40 (1H, brs)

Example 462-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinazolinemethanesulfonate

[0529]

[0530] 2.00 g (4.54 mmol) of the 2-(4-carboxypiperidino)-4-(3,4methylenedioxybenzyl)amino-6-chloroquinazoline prepared in Example222 was dissolved in a mixture comprising 25 ml of tetrahydrofuran and25 ml of ethanol under heating, followed by the dropwise addition of0.31 ml (4.78 mmol) of methanesulfonic acid. The obtained mixture wascooled by allowing to stand to precipitate crystals. The crystals wererecovered by filtration, washed with tetrahydrofuran, and air-dried togive 2.21 g of the title compound.

[0531] molecular formula; C₂₂H₂₁N₄O₄Cl.CH₄O₃S

[0532] yield (%); 91

[0533] m.p. (° C.) ; 265˜266

[0534] NMR δ (DMSO-d₆);

[0535] 1.59 (2H, m), 1.97 (2H, m), 2.32 (3H, s), 2.65 (1H, m), 3.3 (2H,m), 4.40 (2H, m), 4.68 (2H, d, J=5.6 Hz), 5.98 (2H, s), 6.87 (1H, d,J=8.0 Hz), 6.90 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.98 (1H, d, J=1.6 Hz), 7.67(1H, d, J=8.8 Hz), 7.84 (1H, dd, J=8.0 Hz, 2.0 Hz), 8.42 (1H, d, J=2.0Hz), 9.95 (1H, brs), 11.76 (1H, brs), 12.37 (1H, brs)

Example 472-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0536]

[0537] 20 ml of ethanol and 2.0 ml of a 1N aqueous solution of sodiumhydroxide were added to 318 mg of2-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline.The obtained mixture was stirred at 50° C. for 30 minutes andneutralized with 1N hydrochloric acid. The crystal thus precipitated wasrecovered by filtration and purified by silica gel column chromatography(chloroform/methanol) to give 116 mg of the title compound.

[0538] molecular formula; C₂₃H₂₁N₅O₄

[0539] yield (%); 39

[0540] m.p. (° C.); 269˜271

[0541] Mass m/e; 432 (M+1)

[0542] NMR δ (DMSO-d₆);

[0543] 1.40 (2H, m), 1.79 (2H, m), 2.41 (1H, m), 3.04 (1H, dt, J=11.2Hz, 1.2 Hz), 4.55 (2H, d, J=5.6 Hz), 4.57 (2H, m), 5.95 (2H, s), 6.82(1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.94 (1H, s), 7.25 (1H, d,J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz), 8.53 (1H, s), 8.72 (1H, t, J=5.6 Hz)

Example 482-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline

[0544]

[0545] 30 ml of tetrahydrofuran, 30 ml of ethanol and 14 ml of a 1Naqueous solution of sodium hydroxide were added to 1.0 g of2-(4-ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline.The obtained mixture was stirred at room temperature for 16 hours andneutralized with 1 N hydrochloric acid, followed by the addition of 100ml of water. The crystals thus precipitated were recovered by filtrationand recrystallized from tetrahydrofuran/ethanol/water to give 860 mg ofthe title compound.

[0546] molecular formula; C₂₃H₂₂N₅O₃Cl

[0547] yield (%); 91

[0548] m.p. (° C.); 277˜278 (dec.)

[0549] Mass m/e; 452 (M+1)

[0550] NMR δ (DMSO-d₆);

[0551] 1.40 (2H, m), 1.84 (2H, m), 2.51 (1H, m), 3.05 (2H, dt, J=12 Hz,2.4 Hz), 3.82 (3H, s), 4.59 (2H, d, J=5.6 Hz), 4.63 (2H, m), 7.08 (1H,d, J=8.4 Hz), 7.28 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.0 Hz),7.45 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.54 (1H, d,J=2.0 Hz), 8.79 (1H, t, J=5.6 Hz)

Example 49 Sodium2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline

[0552]

[0553] 1.00 g (2.21 mmol) of the 2-(4-carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline prepared in Example228 was dissolved in a mixture comprising 30 ml of tetrahydrofuran and40 ml of ethanol under heating, followed by the addition of 2.3 ml of a1N aqueous solution of sodium hydroxide and 100 ml of water. Theobtained mixture was concentrated in a vacuum to precipitate crystals.The crystals were recovered by filtration, washed with water, andair-dried to give 0.45 g of the title compound.

[0554] molecular formula; C₂₃H₂₁N₅O₃ClNa

[0555] yield (%); 43

[0556] NMR δ (DMSO-d₆);

[0557] 1.45 (2H, m), 1.75 (2H, m), 2.12 (1H, m), 3.06 (2H, m), 3.81 (3H,s), 4.52 (2H, m), 4.58 (2H, d, J=5.6 Hz), 7.07 (1H, d, J=8.8 Hz), 7.24(1H, d, J=8.4 Hz), 7.32 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.45 (1H, d, J=2.0Hz), 7.69 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.54 (1H, d, J=2.0 Hz), 8.86 (1H,brt, J=5.6 Hz)

Example 502-[N-(3-Carboxypropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0558]

[0559] 20 ml of ethanol and 2.61 ml of a 1N aqueous solution of sodiumhydroxide were added to 389 mng of 2-[N-(3-ethoxycarbonylpropyl)-N-methoxyamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixturewas stirred at room temperature for 4 hours and at 50° C. for 10 minutesand neutralized with 1N hydrochloric acid. The crystals precipitatedwere recovered by filtration, purified by silica gel columnnchromatography (chloroform/methanol) and recrystallized fromethanol/acetone/water to give 305 mg of the title compound.

[0560] molecular formula; C₂₂H₂₁N₅O₄

[0561] yield (%); 84

[0562] m.p. (° C.); 138˜140

[0563] Mass m/e; 420 (M+1)

[0564] NMR δ (CDCl₃(+DMSO-d₆));

[0565] 1.96 (2H, brs), 2.31 (brs), 3.24 (3H, s), 3.76 (2H, brs), 4.67(2H, d, J=5.6 Hz), 5.94 (2H, s), 6.77 (1H, d, J=8.0 Hz), 6.86 (1H, d,J=8.0 Hz), 6.91 (1H, s), 7.58 (1H, brs), 7.61 (1H, d, J=8.4 Hz), 8.48(2H, m)

Examples 51 to 65

[0566] The following compounds were prepared in a similar manner tothose of Examples 222 to 230.

Example 512-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6,7,8-trimethoxyquinazoline

[0567]

[0568] molecular formula; C₂₅H₂₈N₄O₇

[0569] yield (%); 73

[0570] m.p. (° C.); 216˜217

[0571] Mass m/e; 297 (M+1)

[0572] NMR δ (CDCl₃);

[0573] 1.80 (2H, m), 2.05 (2H, m), 2.65 (1H, m), 3.39 (2H, dt, J=10.8Hz, 2.8 Hz), 3.98 (3H, s), 4.07 (3H, s), 4.13 (3H, s), 4.26 (2H, m),4.70 (2H, d, J=6.0 Hz), 5.88 (2H, s), 6.69 (1H, d, J=7.6 Hz), 6.95 (1H,dd, J=7.6 Hz, 1.6 Hz), 7.02 (1H, d, J=1.6 Hz), 8.38 (1H, s), 9.36 (1H,s), 11.24 (1H, t, J=6.0 Hz)

Example 522-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6,7,8-trimethoxyquinazoline

[0574]

[0575] molecular formula; C₂₅H₂₃N₄O₆Cl

[0576] yield (%); 90

[0577] m.p. (° C.); 197˜198

[0578] Mass m/e; 517 (M+1)

[0579] NMR δ (DMSO-d₆) ;

[0580] 1.45 (2H, brs), 1.90 (2H, brs), 2.59 (1H, brs), 3.22 (2H, brs),3.80 (3H, s), 3.90 (6H, s), 3.92 (3H, s), 4.39 (2H, brs), 4.65 (2H, d,J=5.2 Hz), 7.05 (1H, d, J=8.4 Hz), 7.33 (1H, d, J=8.4 Hz), 7.45 (1H, s),7.76 (1H, brs), 10.70 (1H, brs)

Example 532-(4-Carboxypioeridino)-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline

[0581]

[0582] molecular formula; C₂₃H₂₄N₄O₅(436)

[0583] yield (%); 79

[0584] m.p. (° C.); 263 (dec.)

[0585] Mass; 437 (M+1)⁺

[0586] NMR δ (DMSO-d₆);

[0587] 1.51˜1.59 (2H, m), 1.86˜195 (2H, m), 2.59˜2.64 (1H, m) 3.21˜3.28(2H, m), 4.39˜4.44 (2H, m), 4.67 (2H, d, J=5.6 Hz), 5.78 (2H, s), 6.85(1H, d, J=7.6 Hz) , 6.89 (1H, d, J=7.6 Hz), 6.99 (1H, s), 7.42 (1H, dd,J=9.2 Hz, 1.6 Hz), 7.72 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=1.6 Hz), 10.02(1H, br), 11.89 (1H, s)

Example 54 2- (4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-methoxyquinazoline

[0588]

[0589] molecular formula; C₂₃H₂₅N₄O₄Cl (456.930)

[0590] yield (%); 81

[0591] m.p. (° C.); 245 (dec.)

[0592] Mass; 457 (MH⁺)

[0593] NMR;

[0594] 1.3˜1.5 (2H, m), 1.79 (2H, d, J=10 Hz), 2.4˜2.5 (1H, m), 2.91(2H, t, J=11 Hz), 3.81 (3H, s), 4.56 (2H, d, J=13 Hz), 4.60 (2H, d,J=5.7 Hz), 7.09 (1H, d, J=8.6 Hz), 7.18 (1H, dd, J=2.7 Hz, 9.2 Hz), 7.24(1H, d, J=9.2 Hz), 7.32 (1H, dd, J=2.2 Hz, 8.6 Hz), 7.45 (1H, d, J=2.2Hz), 7.49 (1H, d, J=2.7 Hz), 8.42 (1H, t, J=5.7 Hz), 12.15 (1H, brs)

Example 552-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-chloroquinazoline

[0595]

[0596] molecular formula; C₂₂H₂₂N₄O₃Cl₂

[0597] yield (%); 92

[0598] m.p. (° C.) ; 280˜281

[0599] Mass m/e; 461 (M+1)

[0600] NMR δ (DMSO-d₆);

[0601] 1.59 (2H, M), 1.94 (2H brd, J=11.6 Hz), 2.62 (1H, brs), 3.32 (2H,m), 3.79 (3H, s), 4.52 (2H, d, J=13.6 Hz), 4.64 (2H, d, J=4.8 Hz), 6.99(1H, d, J=8.4 Hz), 7.30 (1H, d, J=8.4 Hz), 7.42 (1H, s), 7.69 (1H, d,J=8.8 Hz), 8.00 (1H, d, J=8.8 Hz), 8.51 (1H, s), 10.24 (1H, s), 12.42(1H, s)

Example 56 2-(4-Carboxypiperidino)-4-(benzimidazol-5-yl)methylamino-6-chloroquinazoline

[0602]

[0603] molecular formula; C₂₂H₂₁N₆O₂Cl (436.903)

[0604] yield (%); 99

[0605] m.p. (° C.); 230(dec.)

[0606] Mass; 437 (MH)⁺

[0607] NMR δ (DMSO-d₆);

[0608] 1.3˜1.5 (2H, m), 1.82 (2H, d, J=10 Hz), 2.4˜2.5 (1H, m), 2.98(2H, t, J=11 Hz), 4.60 (2H, d, J=13 Hz), 4.77 (2H, d, J=5.7 Hz), 7.2˜7.3(2H, m), 7.45˜7.6 (3H, m), 8.16 (1H, s), 8.19 (1H, d, J=2.4 Hz), 8.68(1H, t, J=5.7 Hz), 12.17 (1H, brs), 12.33 (1H, brs)

Example 572-(Carboxymethyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0609]

[0610] molecular formula; C₁₈H₁₅N₄O₄Cl

[0611] yield (%); 64

[0612] m.p. (° C.); 260˜261 (dec.)

[0613] Mass m/e; 387 (M+1)

[0614] NMR δ (DMSO-d₆);

[0615] 4.00 (2H, brs), 4.57 (2H, d, J=5.6 Hz), 5.93 (2H, s), 6.79 (1H,d, J=8.0 Hz), 6.86 (1H, d, J=8.0 Hz), 6.95 (1H, s), 7.35 (1H, brs), 7.50(1H, brs), 8.30˜8.50 (2H, m)

Example 582-(3-Carboxypropyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0616]

[0617] molecular formula; C₂₀H₁₉N₄O₄Cl

[0618] yield (%); 88

[0619] m.p. (° C.); 170˜172

[0620] Mass m/e; 415 (M+1)

[0621] NMR δ (DMSO-d₆) ;

[0622] 1.71 (2H, brs), 2.23 (2H, brs), 3.27 (2H, brs), 4.56 (2H, d,J=5.6 Hz), 5.95 (2H, s), 6.82 (3H, m), 6.95 (1H, s), 7.20 (1H, brs),7.46 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.12 (1H, d, J=1.6 Hz)

Example 59 2- (5-Carboxypentyl)amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0623]

[0624] molecular formula; C₂₂H₂₃N₄O₄Cl

[0625] yield (%); 80

[0626] m.p. (° C.); 190˜192

[0627] Mass m/e; 443 (M+1)

[0628] NMR δ (DMSO-d₆);

[0629] 1.25 (2H, brs), 1.47 (4H, brs), 2.16 (2H, brs), 3.31 (2H, brs),4.60 (2H, brs), 5.94 (2H, s), 6.84 (2H, s), 6.96 (1H, s), 7.33 (1H,brs), 7.60 (1H, brs), 8.25 (1H, brs)

Example 602-[N-(3-Carboxypropyl)-N-methylamino]-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0630]

[0631] molecular formula; C₂₁H₂₁N₄O₄Cl

[0632] yield (%); 92

[0633] m.p. (° C.); 143˜144

[0634] Mass m/e; 429 (M+1)

[0635] NMR δ (DMSO-d₆(+CD₃OD));

[0636] 1.79 (2H, brs), 2.20 (2H, brs), 3.21 (3H, s), 3.71 (2H, t, J=7.2Hz), 4.65 (2H, s), 5.95 (2H, s), 6.81 (1H, d, J=8.0 Hz), 6.86 (1H, d,J=8.0 Hz), 6.95 (1H, s), 7.79 (1H, d, J=8.8 Hz), 7.85 (1H, d, J=8.8 Hz),8.49 (1H, s)

Example 612-(N-Carboxymethyl-N-methylamino)-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline

[0637]

[0638] molecular formula; C₂₀H₁₇N₅O₄

[0639] yield (%); 68

[0640] m.p. (° C.); 268˜270

[0641] Mass m/e; 392 (M+1)

[0642] NMR δ (DMSO-d₆);

[0643] 3.11 (3H, s), 4.13 (2H, brs), 4.56 (2H, m), 5.94 (2H, s), 6.83(2H, m), 6.93 (1H, d, J=14.4 Hz), 7.20 (1H, m), 7.66 (1H, m), 8.51 (1H,s), 8.62 (1H, m)

Example 622-[N-Ethyl-N-(3-carboxypropyl)amino]-4-(3,4-methylene-dioxybenzyl)amino-6-cyanoquinazoline

[0644]

[0645] molecular formula; C₂₃H₂₃N₅O₄ (433.468)

[0646] yield (%); 96

[0647] m.p. (° C.) ; 186˜187

[0648] Mass; 434 (M+1)

[0649] NMR δ (DMSOd₆);

[0650] 1.0˜1.15 (3H, br 2 peaks), 1.65˜1.85 (2H, br 2 peaks), 2.1˜2.25(2H, br 2 peaks), 3.57 (4H, brs), 4.58 (2H, d, J=5.7 Hz), 5.96 (2H, s),6.84 (2H, s), 6.93 (1H, s), 7.26 (1H, d, J=8.8 Hz), 7.72 (1H, dd, J=1.8Hz, 8.8 Hz), 8.56 (1H, d, J=1.8 Hz), 8.71 (1H, brs)

Example 632-[N-(3-Carboxypropyl)-N-methylamino]-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline

[0651]

[0652] molecular formula; C₂₂H₂₂N₅O₃Cl

[0653] yield (%); 88

[0654] m.p. (° C.); 108˜109

[0655] Mass; 440 (M+1)

[0656] NMR δ (DMSOd₆);

[0657] 1.73 (2H, brs), 2.13 (2H, brs), 3.11 (3H, s), 3.63 (2H, brs),3.82 (3H, s), 4.61 (2H, d, J=5.6 Hz), 7.07 (1H, d, J=8.4 Hz), 7.27 (1H,d, J=8.8 Hz), 7.31 (1H, d, J=8.4 Hz), 7.43 (1H, s), 7.72 (1H, s), 8.55(1H, s), 8.74 (1H, brt, J=5.6 Hz), 12.02 (1H, brs)

Example 642-(4-Carboxypiperidino)-4-(benzimidazol-5-yl)methylamino-6-cyanoquinazoline

[0658]

[0659] molecular formula; C₂₃H₂₁N₇O₂ (427)

[0660] yield (%); 50

[0661] m.p. (° C.); >290

[0662] Mass; 428 (M⁺+1)

[0663] NMR δ (DMSO-d₆);

[0664] 1.29˜1.42 (2H, m), 1.76˜2.20 (2H, m), 2.39˜2.51 (2H, m),2.99˜3.07 (3H, m), 4.60˜4.64 (2H, m), 4.76 (2H, d, J=5.6 Hz), 7.23 (1H,d, J=8.4 Hz), 7.25 (1H, d, J=8.8 Hz), 7.51 (1H, d, J=8.4 Hz), 7.56 (1H,s), 7.71 (1H, dd, J=8.4 Hz, 1.6 Hz), 8.14 (1H, s), 8.57 (1H, d, J=1.6Hz), 8.82 (1H, brt, J=5.6 Hz)

Example 652-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-carbamoylquinazoline

[0665]

[0666] molecular formula; C₂₃H₂₃N₅O₅ (449)

[0667] yield (%); 6

[0668] m.p. (° C.); 180˜182 (dec.)

[0669] Mass; 450 (M+1)

[0670] NMR δ (DMSO-d₆);

[0671] 1.39 (2H, m), 1.81 (2H, m), 2.48 (1H, m), 2.99 (2H, m) , 4.55(2H, d, J=5.6 Hz), 4.62 (2H, m), 5.93 (2H, s), 6.81 (1H, d, J=7.6 Hz),6.85 (1H, dd, J=7.6 Hz), 6.95 (1H, d, J=1.6 Hz), 7.20 (1H, d, J=8.8 Hz),7.27 (1H, br), 7.71 (1H, br), 7.92 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.57 (1H,d, J=2.0 Hz), 8.59 (1H, brt, J=5.6 Hz), 12.09 (1H, br)

Example 662-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)oxy-6-chloroquinazoline

[0672]

[0673] molecular formula; C₂₂H₂₀ClN₃O₅

[0674] yield (%); 84

[0675] m.p. (° C.); 145˜147

[0676] Mass m/e; 442 (M+1)

[0677] NMR δ (DMSO-d₆) ;

[0678] 1.47 (2H, m), 1.88 (2H, m), 2.49 (1H, m), 3.10 (2H, brt, J=13.2Hz), 4.60 (2H, brd, J=13.2 Hz), 5.43 (2H, s), 6.01 (2H, s), 6.91 (1H, d,J=8.0 Hz), 7.02 (1H, d, J=8.0 Hz), 7.11 (1H, s), 7.39 (1H, d, J=8.8 Hz),7.61 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.77 (1H, d, J=2.4 Hz)

Example 67 2-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)-thio-6-chloroquinazoline

[0679]

[0680] molecular formula; C₂₂H₂₀ClN₃O₄S

[0681] yield (%); 98

[0682] m.p. (° C.); 153˜154

[0683] Mass m/e; 458 (M+1)

[0684] NMR δ (DMSO-d₆);

[0685] 1.50 (2H, m), 1.82 (2H, m), 2.39 (1H, brs), 3.18 (2H, m), 4.48(2H, s), 4.55 (2H, brs), 5.96 (2H, s), 6.82 (1H, d, J=8.0 Hz), 6.92 (1H,d, J=8.0 Hz), 6.99 (1H, s), 7.41 (1H, brd, J=8.8 Hz), 7.62 (1H, brd,J=8.8 Hz), 7.69 (1H, brs)

Example 682-(4-Nitroxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinazoline

[0686]

[0687] molecular formula; C₂₁H₂₀ClN₅O₅

[0688] yield (%); 11

[0689] m.p. (° C.); oily substance

[0690] Mass m/e; 458 (MH⁺)

[0691] NMR δ (CDCl₃);

[0692] 1.71˜1.82(2H, m), 2.02˜2.10(2H, m), 3.56˜3.63(2H, m),4.39˜4.44(2H, m), 4.66(2H, d, J=5.2 Hz), 5.18˜5.22(1H, m), 5.61(1H, brt,J=5.2 Hz), 5.96(2H, s), 6.79(1H, d, J=7.6 Hz), 6.84(1H, dd, J=7.6 Hz,1.2 Hz), 6.87 (1H, d, J=1.2 Hz), 7.39 (1H, d, J=8.8 Hz), 7.43˜7.47(2H,m)

Example 692-(4-Carboxypiperidino)-4-(3,4-methylenedioxybenzyl)-amino-6-chloroquinoline

[0693]

a) 2-(4-Ethoxycarbonylpiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-chloroquinoline

[0694] A reaction of a mixture comprising 130 mg of2,6-dichloro-4-(3,4-methylenedioxybenzyl)-aminoquinoline, 500 μl ofethyl isonipecotate and 1 ml of N-methyl-2-pyrrolidone was conducted onan oil bath at 150° C. for 3 hours. The reaction mixture was cooled,followed by the addition of water. The resulting mixture was extractedwith ethyl acetate and the ethyl acetate layer was washed with water anda saturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography with 20 to 50% ethyl acetate/hexane to give150 mg of the title compound.

[0695] NMR δ (CDCl₃);

[0696] 1.26(3H, t, J=7.1 Hz), 1.70˜1.81(2H, m), 1.95˜2.02 (2H, m), 2.54(1H, tt, J=11.2 Hz, 3.8 Hz), 2.97˜3.06 (2H, m), 4.14 (2H, q, J=7.1 Hz),4.32˜4.39(4H, m), 4.86 (1H, t, J=5.5 Hz), 5.98 (3H, s), 6.81 (1H, d,J=7.7 Hz), 6.84˜6.89(2H, m), 7.39 (1H, dd, J=9.0 Hz, 2.4 Hz), 7.47 (1H,d, J=2.4 Hz), 7.55 (1H, d, J=9.0 Hz)

b)2-(4-Carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-chloroquinoline

[0697] A reaction of a mixture comprising 150 mg of the compoundprepared in the step (a), 1 ml of a 1N aqueous solution of sodiumhydroxide and 10 ml of ethanol was conducted on an oil bath at 60° C.for 2 hours. The reaction mixture was concentrated, followed by theaddition of water. The resulting mixture was neutralized by the additionof 1 ml of 1N hydrochloric acid to precipitate crystals. The crystalswere recovered by filtration, washed with water, and dried to give 130mg of the title compound.

[0698] molecular formula; C₂₃H₂₂ClN₃O₄

[0699] yield (%); 92

[0700] m.p. (° C.) ; 235˜237

[0701] Mass m/e; 440 (M+1)

[0702] NMR δ (DMSO-d₆);

[0703]1.37˜1.50 (2h, m), 1.77˜1.86 (2H, m), 2.89˜3.00 (2H, br, 3 peak),4.20˜4.28 (2H, br, 2 peak), 4.42 (2H, d, J=5.7 Hz), 5.96 (2H, s), 5.97(1H, s), 6.85 (1H, d, J=7.9 Hz), 6.92 (1H, dd, J=7.9 Hz, 1.5 Hz), 6.98(1H, d, J=1.5 Hz), 7.42 (2H, brs), 7.58 (1H, brs), 8.15 (1H, brs)

Example 702-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzyl)-amino-6-chloroquinoline

[0704]

[0705] The title compound was prepared in a similar manner to that ofExample 255.

[0706] molecular formula; C₂₃H₂₃Cl₂n₃O₃

[0707] m.p. (° C.); 282˜283

[0708] Mass m/e; 460 (M+1)

[0709] NMR δ (DMSO-d₆) ;

[0710] 1.36˜1.48 (2H, m), 1.76˜1.84 (2H, m), 2.43˜2.53 (1H, m), 2.91(2H, t, J=11.2 Hz), 4.26 (2H, brd, J=13.2 Hz), 4.44 (2H, d, J=5.9 Hz),5.97 (1H, s), 7.10 (1H, d, J=8.6 Hz), 7.36 (1H, dd, J=8.6 Hz, 2.2 Hz),7.38 (2H, s), 7.50 (2H, brs and d, J=2.2 Hz), 8.11 (1H, s)

Example 71 2- (3,4-Methylenedioxybenzylamino)-4-(4-carboxypiperidino)-6-chloroquinoline

[0711]

[0712] 130 mg of the title compound was prepared from 140 mg of the4,6-dichloro-2-(3,4-methylenedioxybenzyl)-aminoquinoline prepared in thestep (b) of Example 253 as a by-product in a similar manner to that ofExample 255.

[0713] molecular formula; C₂₃H₂₂ClN₃O₄

[0714] yield (%); 99

[0715] m.p. (° C.); 270˜272

[0716] Mass m/e; 440 (M+1)

[0717] NMR δ (DMSO-d₆);

[0718] 1.78˜1.89 (2H, m), 1.96˜2.04 (2H, m), 2.70˜2.79 (2H, m),3.26˜3.36 (2H, m), 4.49 (2H, d, J=5.7 Hz), 5.96 (2H, s), 6.37 (1H, s),6.85 (2H, s), 6.94 (1H, s), 7.37 (1H, t, J=5.7 Hz), 7.41 (1H, dd, J=8.8Hz, 2.4 Hz), 7.46 (1H, d, J=8.8 Hz), 7.60 (1H, d, J=2.4 Hz)

Example 722-(4-Carboxypiperidino)-4-(3-chloro-4-methoxy-benzyl)amino-6-cyanoquinazoline

[0719]

a)2-(4-Ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzylamino)-6-cyanoquinoline

[0720] A mixture comprising 750 mg of2-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinoline, 1.6 ml ofisonipecotic acid and 5 ml of N-methyl-2-pyrrolidone was heated on anoil bath at 130° C. for 3 hours and cooled, followed by the addition ofwater. The resulting mixture was extracted with ethyl acetate and theethyl acetate layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate, andconcentrated. The residue was subjected to silica gel columnchromatography (20 to 40% ethyl acetate/hexane) and thereafterrecrystallized from ethyl acetate/hexane to give 860 mg of the titlecompound.

[0721] NMR δ (CDCl₃);

[0722] 1.26 (3H, t, J=7.1 Hz), 1.68˜1.79 (2H, m), 1.95˜2.03 (2H, m),2.58 (1H, tt, J=11.0 Hz, 4.0 Hz), 3.03˜3.12 (2H, m), 3.92 (3H, s), 4.15(2H, q, J=7.1 Hz), 4.36˜4.43 (4H, m), 5.08 (1H, t, J=5.1 Hz), 5.94 (1H,s), 6.95 (1H, d, J=8.4 Hz), 7.26 (1H, dd, J=8.4 Hz, 2.2 Hz), 7.42 (1H,d, J=2.2 Hz), 7.55˜7.61 (2H, m), 7.88 (1H, s)

b)2-(4-Carboxypiperidino)-4-(3-chloro-4-methoxybenzylamino)-6-cyanoquinoline

[0723] A mixture comprising 500 mg of the compound prepared in the step(a), 2 ml of a 1N aqueous solution of sodium hydroxide, 20 ml oftetrahydrofuran and 25 ml of ethanol was reacted at 50° C. for 2 hours,followed by the addition of 2 ml of 1N hydrochloric acid. About 20 ml ofthe solvents was distilled away to precipitate crystals. The crystalswere recovered by filtration, washed with water and ethyl acetate, anddried to give 460 mg of the title compound.

[0724] molecular formula; C₂₄H₂₃ClN₄O₃

[0725] yield (%); 98

[0726] m.p. (° C.); 274˜276 (dec.)

[0727] NMR δ (DMSO-d₆);

[0728] 1.35˜1.47 (2H, m), 1.78˜1.87 (2H, m), 2.47˜2.56 (1H, m),2.95˜3.04 (2H, m), 3.81 (3H, S), 4.30˜4.39 (2H, m), 4.46 (2H, d, J=5.7Hz), 6.01 (1H, s), 7.11 (1H, d, J=8.6 Hz), 7.37 (1H, dd, J=8.6 Hz, 2.2Hz), 7.40 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=2.2 Hz), 7.65 (1H, dd, J=8.8Hz, 1.6 Hz), 7.68 (1H, t, J=5.7 Hz), 8.55 (1H, d, =J=1.6 Hz), 12.20 (1H,brs)

Example 732-(4-Carboxypiperidino)-8-(3,4-methylenedioxybenzyl)-aminopyrido[2,3-d]pyrimidine

[0729]

a) 2-(4-ethoxycarbonylpiperidino)-8-(3,4-methylenedioxybenzylamino)pyrido[2,3-d]pyrimidine

[0730] 41 mg of triethylamine and 190 mg of ethyl isonipecotate wereadded to a solution of 127 mg of2-chloro-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidine in 8ml of tetrahydrofuran. The obtained mixture was refluxed for 2 hours,followed by the addition of water. The resulting mixture was extractedwith chloroform twice. The organic layers were combined, dried overmagnesium sulfate, and distilled to remove the solvent. The residue waspurified by silica gel chromatography (with ethyl acetate) to give 175mg of the title compound (in a yield of 100%).

b)2-(4-carboxypiperidino)-8-(3,4-methylene-dioxybenzyl)aminopyrido[2,3-d]pyrimidine

[0731] 1.56 ml of 1N sodium hydroxide was added to a solution of 170 mgof2-(4-ethoxycarbonylpiperidino)-8-(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidinein 10 ml of ethanol. The obtained mixture was stirred at roomtemperature for 6 hours and neutralized by the addition of 1Nhydrochloric acid and water. The crystals thus precipitated wererecovered by filtration, whereby 121 mg of the title compound wasobtained.

[0732] molecular formula; C₂₁H₂₁N₅O₄

[0733] yield (%); 76

[0734] m.p. (° C.); 255˜256

[0735] Mass m/e; 408 (M+1)

[0736] NMR δ (DMSO-d₆);

[0737] 1.39 (2H, m), 1.80 (2H, m) , 2 51 (1H, m) 3.01 (2H, brt, J=11.2Hz), 4.56 (2H, d, J=5.6 Hz), 4.61 (2H, brd, J=12.8 Hz), 5.94 (2H, s),6.82 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.0 Hz), 6.93 (1H, s), 7.03 (1H,dd, J=8.0 Hz, 4.4 Hz), 8.38 (1H, dd, J=8.0 Hz, 1.6 Hz), 8.61 (1H, dd,J=4.4 Hz, 1.6 Hz), 8.70 (1H, t, J=5.6 Hz), 12.16 (1H, brs)

Examples 74 to 82

[0738] The following compounds were prepared in a similar manner tothose of Examples 88 to 94.

Example 742-(4-Carboxypiperidino)-4-(3,5-dichloro-4-methoxybenzylamino)-6-cyanoquinazoline

[0739]

[0740] molecular formula; C₂₃H₂₁Cl₂N₅O₃

[0741] yield (%); 98

[0742] m.p. (° C.); 255˜256 (dec.)

[0743] Mass m/e; 486 (M+1)⁺

[0744] NMR δ (DMSO-d₆);

[0745] 1.36 (2H, brm), 1.80 (2H, brm), 2.52 (1H, m), 3.03 (2H, m), 3.78(3H, s), 4.59 (2H, d, J=6.0 Hz), 4.59- (2H, brm), 7.29 (1H, d, J=8.8Hz), 7.50 (2H, s), 7.75 (1H, dd, J=8.8 Hz, 1.6 Hz), 8.53 (1H, d, J=1.6Hz), 8.85 (1H, brt, J=6.0 Hz), 12.18 (1H, brs)

Example 752-[N-[2-(2-Pyridyl)ethyl]methylamino]-4-(3,4-methylene-dioxybenzyl)]amino-6-chloroquinazolinedihydrochloride

[0746]

[0747] molecular formula; C₂₄H₂₂ClN₅O₂.2HCl

[0748] yield (%); 94

[0749] m.p. (° C.); 234˜236 (dec.)

[0750] Mass m/e; 448 (M+1)⁺

[0751] NMR δ (DMSO- d₆);

[0752] 3.2˜3.3 (5H, br), 4.12 (2H, br), 4.61 (2H, br), 5.97 (2H, s),6.82 (1H, brd), 6.88 (1H, brd), 7.00 (1H, s), 7.74 (2H, br), 7.86 (1H,dd, J=9.2 Hz, 2.0 Hz), 8.01 (1H, br), 8.26 (1H, br), 8.57 (1H, d, J=2.0Hz), 8.74 (1H, br), 10.16 (1H, brs), 12.12 (1H, brs)

Example 76 2-(4-Carboxypiperidino)-4-(3,4-dihydroxybenzyl)amino-6-chloroquinazoline

[0753]

[0754] molecular formula; C₂₁H₂₁ClN₄O₄

[0755] yield (%); 95

[0756] m.p. (° C.); 216˜218 (dec.)

[0757] Mass m/e; 429 (MH⁺)

[0758] NMR δ (DMSO-d₆);

[0759] 1.38˜1.47 (2H, m), 1.80˜1.84 (2H, m), 2.44˜2.49 (1H, m),2.93˜3.00 (2H, m), 4.48 (2H, d, J=5.6 Hz), 4.57˜4.61 (2H, m), 6.60˜6.65(2H, m), 6.74 (1H, d, J=1.6 Hz), 7.24 (1H, d, J=8.8 Hz), 7.46 (1H, dd,J=8.8 Hz, 2.0 Hz), 8.15 (1H, d, J=2.0 Hz), 8.48 (1H, brs), 8.675 (1H,s), 8.75 (1H, s), 12.14 (1H, brs)

Example 772-(4-Carboxypiperidino)-4-(5-nitroxypentyl)amino-6-chloroquinazoline

[0760]

[0761] molecular formula; C₁₉H₂₄ClN₅O₅

[0762] yield (%); 80

[0763] m.p. (° C.); 176˜179 (dec.)

[0764] Mass m/e; 438 (MH⁺)

[0765] NMR δ (DMSO-d₆);

[0766] 1.34˜2.00 (10H, m), 2.57˜2.64 (1H, m), 3.18˜3.59 (4H, m),4.44˜4.58 (4H, m), 7.72˜7.86 (2H, m), 8.39˜8.41 (1H, m), 12.31 (2H, brs)

Example 782-(Carboxymethyl)methylamino-4-(3-pyridylmethyl)amino-6-chloroquinazoline

[0767]

[0768] molecular formula; C₁₇H₁₆ClN₅O₂

[0769] yield (%); 97

[0770] m.p. (° C.) ; 222˜223

[0771] Mass m/e; 358 (M+1)

[0772] NMR δ (DMSO-d₆);

[0773] 3.10 (3H, s), 4.22 (2H, brs), 4.63 (2H, brs), 7.31 (2H, m), 7.48(1H, m), 7.72 (1H, m), 8.14 (1H, d, J=2.4 Hz), 8.43 (1H, d, J=4.8 Hz),8.59 (1H, m), 8.66 (1H, brs)

Example 792-[N-(3-Carboxypropyl)-N-methylamino]-4-(3-pyridylmethyl)amino-6-chloroquinazoline

[0774]

[0775] molecular formula; C₁₉H₂₀ClN₅O₂

[0776] yield (%); 41

[0777] m.p. (° C.); 110˜112

[0778] Mass m/e; 386 (M+1)

[0779] NMR δ (DMSO-d₆);

[0780] 1.67 (2H, brs), 2.09 (2H, m), 3.02 (3H, s), 3.53 (2H, t, J=6.8Hz), 4.67 (2H, d, J=5.6 Hz), 7.24 (2H, d, J=8.8 Hz), 7.31 (1H, dd, J=8.0Hz, 4.8 Hz), 7.47 (1H, dd, J=8.8 Hz, 2.0 Hz), 7.73 (1H, d, J=8.0 Hz),8.13 (1H, d, J=2.0 Hz), 8.41 (1H, d, J=4.8 Hz), 8.58 (1H, s), 8.62 (1H,brs), 12.04 (1H, brs)

Example 802-(4-Carboxypiperidino)-4-(2-pyridylmethyl)amino-6-chloroquinazoline

[0781]

[0782] molecular formula; C₂₀H₂₀ClN₅O₂

[0783] yield (%); 92

[0784] m.p. (° C.); 235˜237

[0785] Mass m/e; 398 (M+1)

[0786] NMR δ (DMSO-d₆);

[0787] 1.25˜1.45 (2H, m), 1.71˜1.83 (2H, m), 2.45˜2.54 (1H, m),2.93˜3.10 (2H, m), 4.37˜4.48 (2H, m), 4.77 (2H, d, J=5.5 Hz), 7.25 (1H,dd, J=7.7 Hz, 5.0 Hz), 7.37 (1H, d, J=7.7 Hz), 7.48 (1H, brs), 7.63 (1H,brs), 7.73 (1H, td, J=7.7 Hz, 1.6 Hz), 8.34 (1H, brs), 8.51 (1H, brd,J=5.0 Hz), 12.23 (1H, brs)

Example 812-(4-Carboxypiperidino)-4-(3-pyridylmethyl)amino-6-chloroquinazoline

[0788]

[0789] molecular formula; C₂₀H₂₀ClN₅O₂

[0790] yield (%); 93

[0791] m.p. (° C.); >250

[0792] Mass m/e; 398 (M+1)

[0793] NMR δ (DMSO-d₆) ;

[0794] 1.45˜1.60 (2H, m), 1.84˜1.97 (2H, m), 2.58˜2.68 (1H, m),3.25˜3.45 (2H, m), 4.45˜4.54 (2H, m), 4.80 (2H, d, J=5.7 Hz), 7.41 (1H,dd, J=7.9 Hz, 4.8 Hz), 7.82 (1H, dd, J=9.0 Hz, 2.0 Hz), 7.86˜7.96 (2H,m), 8.50 (1H, d, J=4.8 Hz), 8.55 (1H, d, J=1.6 Hz), 8.69 (1H, s)

Example 822-(4-Carboxypiperidino)-4-(4-pyridylmethyl)amino-6-chloroquinazoline

[0795]

[0796] molecular formula; C₂₀H₂₀ClN₅O₂

[0797] yield (%); 89

[0798] m.p. (° C.); 167˜168

[0799] Mass m/e; 398 (M+1)

[0800] NMR δ (DMSO-d₆);

[0801] 1.24˜1.36 (2H, m) , 1.68˜1.77 (2H, m), 2.40˜2.49 (1H, m),2.86˜2.96 (2H, m), 4.42˜4.50 (2H, m), 4.66 (2H, d, J=5.7 Hz), 7.28 (1H,d, J=9.0 Hz), 7.34 (2H, d, J=6.0 Hz), 7.51 (1H, dd, J=9.0 Hz, 2.4 Hz),8.18 (1H, d, J=2.4 Hz), 8.47 (2H, d, J=6.0 Hz), 8.74 (1H, t, J=5.7 Hz)

Example 83 2-(4-Cyanopiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline

[0802]

[0803] 75 ml of thionyl chloride and 150 ml of acetonitrile were addedto 3.8 g (0.0086 mol) of2-(4-carbamoylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The mixture thus obtained was heated underreflux for one hour. The reaction mixture was distilled under a reducedpressure to remove the solvent. A saturated aqueous solution of sodiumhydrogencarbonate and triethylamine were added to the residue and theresultant mixture was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate, filtered and distilled under a reducedpressure to remove the solvent. The obtained residue was purified by asilica gel column chromatography (ethyl acetate-n-hexane) andrecrystallized from chloroform-n-hexane to give 3.1 g of the titlecompound.

[0804] molecular formula; C₂₂H₂₀ClN₅O₂

[0805] yield (%); 85

[0806] m.p. (° C.); 169˜170

[0807] NMR δ (CDCl₃);

[0808] 1.88 (2H, m), 1.95 (2H, m), 2.87 (1H, m), 3.73 (2H, m), 4.25 (2H,m), 4.67 (2H, d, J=5.6 Hz), 5.65 (1H, t, J=5.6 Hz), 5.97 (2H, s), 6.79(1H, d, J=8.0 Hz), 6.84 (1H, dd, J=8.0 Hz, 1.6 Hz), 6.87 (1H, d, J=1.6Hz), 7.39 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=2.4 Hz), 7.46 (1H, dd, J=8.8Hz, 2.4 Hz)

Example 842-[4-(1H-tetrazol-5-yl)piperidinol-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazolinehydrochloride

[0809]

[0810] 10 ml of toluene was added to a mixture comprising 0.50 g (0.0012mol) of2-(4-cyanopiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazolineand 0.50 g (0.0024 mol) of trimethyl stannylazide. The mixture thusobtained was heated under reflux for two days. The reaction mixture wasdistilled under a reduced pressure to remove the solvent. The residuewas suspended in 10 ml of ethanol, followed by the addition of 10 ml of1N hydrochloric acid. The mixture thus obtained was stirred at roomtemperature for several hours. The mixture was filtered to recover thecrystal. The crystal was washed with water and air-dried to give 0.60 gof the title compound.

[0811] molecular formula; C₂₂H₂₁ClN₈O₂.HCl

[0812] yield (%); quantitative

[0813] m.p. (° C.); 212˜214

[0814] Mass m/e; 465 (M+1)⁺

[0815] NMR δ (DMSO-d₆);

[0816] 1.80 (2H, m), 2.17 (2H, m), 3.45 (2H, m), 4.62 (2H, m), 4.69 (2H,d, J=5.6 Hz), 5.97 (2H, s), 6.86 (1H, d, J=7.6 Hz), 6.91 (1H, dd, J=7.6Hz, 1.6 Hz), 7.01 (1H, d, J=1.6 Hz), 7.84 (1H, dd, J=8.8 Hz, 1.6 Hz),7.88 (1H, d, J=8.8 Hz), 8.51 (1H, d, J=1.6 Hz), 10.13 (1H, brs), 12.28(1H, brs)

Example 854-Amino-6,7-dimethoxy-2-[4-(5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonyl)-piperazin-1-yl]-quinazolineHydrochloride

[0817] A solution of 5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonylchloride (5.17 g, 0.022 mole) in dioxane (35 ml. was added to a solutionof 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (6.35 g., 0.022mole) in diexane (190 ml.). The resultant mixture was stirred at refluxfor 1 hour, and then at 23° C. for 18 hours. Filtration gave the titlecompound; m.p. 281°-284° C. (dec.) after crystallization from methanol.

[0818] Anal. Calcd. for C₂₀H₂₄N₈O_(s).HCl: C, 45.76; H, 4.80; Cl, 6.75;N, 21.35. Found: C, 45.49; H, 4.65; Cl., 7.10; N, 21.06.

[0819] The 5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonyl chloridestarting material was obtained in the following manner.

A 5-Ethoxycarbonylamino-1,2,3-thiadiazole-4-carboxylic Acid

[0820] A suspension of sodium thiocyanate (24.30 g, 0.30 mole) inacetonitrile (120 ml), maintained at 19° C., was treated dropwise over22 minutes with a solution of ethyl chloroformate (28.7 ml, 0.30 mole)in acetonitrile (25 ml). The resultant mixture was stirred for 25minutes at 20° C. and then ethyl diazoacetate (31.5 ml, 0.30 mole) wasadded. After stirring for 24 hours, 6.0 N hydrochloric acid (300 ml) wasadded with cooling. Acetonitrile solvent was removed in vacuo and theresidual aqueous suspension was extracted several times with ether.Combined ether extracts were washed with water, dried (Na₂SO₄) andevaporated to leave 51.0 g of ethyl5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carboxylate. This ester washydrolyzed by refluxing for 6 hours in a mixture of ethanol (80 ml) andaqueous 6 N hydrochloric acid (400 ml) to yield the title acid; m.p.179°-180° dec. after crystallization from nitromethane.

B 5-Ethoxycarbonylamino-1,2,3-thiadiazole-4-carbonyl Chloride

[0821] Oxalyl chloride (8.76 g, 0.069 mole) was added slowly to astirred suspension of5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carboxylic acid (5.00 g, 0.023mole) in dry ether (65 ml) containing three drops ofN,N-dimethylformamide. Tetrahydrofuran was added and the resultant clearsolution was stirred at 23° C. for 2 hours. Filtration and subsequentevaporation gave a residue which was triturated under petroleum ether toyield the title acid chloride (5.17 g, 96%) m.p. 129°-133.5° C.

Example 864-Amino-6,7-dimethoxy-2-[4-(1,2,3-thiadiazole-4-carbonyl)piperazin-1-yl)quinazolineHydrochloride

[0822] The title compound was prepared by reacting1,2,3-thiadiazole-4-carbonyl chloride (D. L. Pain and R. Slack, J. Chem.Soc., 5166 (1965)) and4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline according to theprocedure of Example 1. After crystallization from aqueous ethanol, thetitle compound melted at 270° C. (dec.).

[0823] Anal. Calcd for C₁₇H₁₉N₇O₃S.HCl: C, 46.62; H, 4.60; N, 22.39; S,7.32. Found: C, 46.43; H, 4.39; N, 22.58; S, 7.14 (corrected for 6.08%water of hydration).

Example 874-Amino-6,7-dimethoxy-2-[4-(1,2,3-thiadiazole-5-carbonyl)piperazin-1-yl)quinazolineHydrochloride

[0824] A solution of potassium hydroxide (3.30 g.) in water (7 ml.) wasadded to a solution of ethyl 1,2,3-thiadiazole-5-carboxylate (8.00 g.)in ethanol (25 ml.). The mixture was stirred at 23° C. for 2 hours, andthen was worked up to yield potassium 1,2,3-thiadiazole-5-carboxylate. Asuspension of this salt (3.00 g.) in toluene (25 ml.) was treated at 0°C. with oxalyl chloride (1.6 ml.), stirred at 0° C. for 1 hour, and thenwas worked up to yield 1,2,3-thiadiazole-5-carbonyl chloride.

[0825] Reaction of a 1, 2, 3-thiadiazole-5-carbonyl chloride and4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline according to theprocedure of Example 1 provided the title compound having a meltingpoint of 295°-297° C. after crystallization from aqueous ethanol.

[0826] Anal. Calcd. for C₁₇H₁₉N₇O₃S.HCl: C, 46.62; H, 4.60; N, 22.39; S,7.32. Found: C, 46.91, H, 4.51; N, 21.91; S, 7.39 (corrected for 2.6%water of hydration).

Example 884-Amino-6,7-dimethoxy-2-[4-(5-methyl-1,2,3-thiadiazole-4-carbonyl)-piperazin-1-yl)quinazolineHydrochloride

[0827] Hydrolysis of ethyl 5-methyl-1,2,3-thiadiazole-4-carboxylate (D.L. Pain and R. Sleck, J. Chem. Soc., 5166 (1965)) and subsequenttreatment of the acid with oxalyl chloride according to the method ofExample 3 provides 5-methyl-1,2,3-thiadiazole-4-carbonyl chloride.

[0828] Reaction of the carbonyl chloride and4-amino-6,7-dimethoxy-2-(1-piperizinyl)-quinazoline according to theprocedure of Example 1 provides the title compound.

Example 894-Amino-6,7-dimethoxy-2-[4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)-piperazin-1-yl-quinazolinehydrochloride

[0829] A solution of 5-methylthio-1,3,4-oxadiazole-2-carbonyl chloride(0.601 g., 3.36 mole) in dioxane (10 ml) was added to a solution of4-amino-6,7-dimethoxy-2-(1-piperizinyl)quinazoline (0.972 g., 3.36mmole) in dioxane (100 ml.). The resultant mixture was stirred at roomtemperature for 65 hours, then was heated at reflux for 30 minutes.Filtration gave the title compound (1.56 g.). Recrystallization frommethanol gave a product having a M.P. of 280°-285° C. withdecomposition.

[0830] Anal. Calcd for C₁₈H₂₁N₇O₄S.HCl: C, 46.20, H, 4.74; Cl, 7.58; N,20.96; S, 6.85. Found: C, 46.34, H, 4.89; Cl, 7.59; N, 20.38; S, 6.58.

Example 904-Amino-6,7-dimethoxy-2-[4-(5-ethylthio-1,3,4-oxadiazole-2-carbonyl)-piperazin-1-yl-quinazolinehydrochloride

[0831] The title compound was prepared from5-ethylthio-1,3,4-oxadiazole-2-carbonyl chloride (0.79 g., 4.1 mmole)and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)-quinazoline (1.19 g., 4.1mmole) following the procedure described in Example 1. The product had aM.P. of 246°-248.5° C.

[0832] Anal. Calcd for C₁₉H₁₃N₇O₄S.HCl: C, 47.34, H, 5.02; N, 20.34; S,6.65. Found: C, 47.37; H, 4.76; N, 20.15; S, 6.71 (corrected for 4.11%H₂O).

Example 914-Amino-6,7-dimethoxy-2-[4-(5-isopropylthio-1,3,4-oxadiazole-2-carbonyl)-piperazin-1-yl]-quinazolinehydrochloride

[0833] The title compound was prepared from5-isopropylthio-1,3,4-oxadiazole-2-carbonyl chloride (1.54 g., 7.5mmole) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.1 g.,7.5 mmole) following the procedure of Example 1. The product had a M.P.of 260°-263° C. with decomposition.

[0834] Anal. Calcd for C_H₂₃N₇O₄S.HCl: C, 48.43; H, 5.28; N, 19.77.Found: C, 48.05; H, 5.20; N, 19.61.

Example 924-Amino-6,7-dimethoxy-2-[4-(5-n-propylthio-1,3,4-oxadiazole-2-carbonyl)-piperazin-1-yl]-quinazolinehydrochloride

[0835] The title compound was prepared from5-n-propylthio-1,3,4-oxadiazole-2-carbonyl chloride (1.68 g., 8.16mmole) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.36 g.,8.16 mmole) following the procedure of Example 1. The product had a M.P.of 230°-245° C. with decomposition.

[0836] Anal. Calcd for C₂₀H_N₇O₄S.HCl: C, 48.43; H, 5.25; N, 19.77.Found: C, 48.11; H, 5.35; N, 19.65.

Example 93 4-Amino-6,7-dimethoxy-2-[4-(5-n-butylthio-1,3,4-oxadiazole-2-carbonyl)-piperazin-1-yl]-quinazolinehydrochloride

[0837] The title compound was prepared from5-n-butylthio-1,3,4-oxadiazole-2-carbonyl chloride and4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline following theprocedure of Example 89.

Example 944-Amino-6,7-dimethoxy-2-[4-(isoxazole-5-carbonyl)-piperazine-1-yl]quinazolineHydrochloride

[0838] A solution of isoxazole-5-carbonyl chloride (1.33 g., 0.01 mole)in dioxane was added to a solution at 30° C. of4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.94 g., 0.01 mole)in dioxane. The mixture was stirred at reflux for three minutes, then atroom temperature for 16 hours. Filtration gave the title compound (4.02g., 94% yield). Recrystallization from aqueous methanol gave a producthaving a m.p. of 270° C. with decomposition.

[0839] Anal. Calcd. for C₁₈H₂₀N₆O₄S.HCl: C, 51.37; H, 5.03; Cl, 8.42; N,19.97. Found: C, 50.86; H, 4.65; Cl, 8.52; N, 19.81 (corrected for 4.30%H₂O).

Example 954-Amino-6,7-dimethoxy-2-[4-(isoxazole-3-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0840] A solution of isoxazole-3-carbonyl chloride (0.753 g., 0.0057mole) in dioxane (20 ml.) was added to a solution of4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.66 g., 0.0057mole) in dioxane (60 ml.). The mixture was stirred at reflux for 30minutes, then at room temperature for 64 hours. Filtration gave thetitle compound which was recrystallized from methanol (1.81 g., 75%yield). The product had a m.p. of 268°-273° C. with decomposition.

[0841] Anal. Calcd. for C₁₈H₂₀N₆O₄HCl: C, 51.37; H, 5.03; Cl, 8.42; N,19.97. Found: C, 50.04; H, 4.86; Cl, 8.66; N, 19.57 (corrected for 3.11%H₂O).

Example 964-Amino-6,7-dimethoxy-2-[4-(isoxazole-4-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0842] A solution of isoxazole-4-carbonyl chloride (1.06 g., 8.08 mmole)in dioxane (8 ml.) was added to a solution at of4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.34 g., 8.08 mmole)in dioxane (200 ml.). The mixture was stirred at room temperature for 20hours. Filtration gave the title compound, which, afterrecrystallization from methanol, had a m.p. of 225°-260° C. withdecomposition.

[0843] Anal. Calcd. for C₁₈H₂₀N₆O₄HCl: C, 51.37; H, 5.03; Cl, 8.42; N,19.97. Found: C, 51.37; H, 4.95; Cl, 8.34; N, 19.95 (corrected for 1.63%H₂O)

Example 974-Amino-6,7-dimethoxy-2-[4-(5-methylisoxazole-3-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0844] A solution of 5-methylisoxazole-3-carbonyl chloride (0.41 g.,2.83 mmole) in dioxane was added to a solution of4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.82 g., 2.83 mmole)in dioxane. The mixture was treated as described in the previous exampleto give the title compound having a m.p. of 271°-273° C. withdecomposition.

[0845] Anal. Calcd. for C₁₉H₂₂N₆O₄HCl H₂O: C, 50.38; H, 5.56; N, 18.56;H₂O, 3.92. Found: C, 50.58; H, 5.40; N, 18.86; H₂O, 3.72.

Example 984-Amino-6,7-dimethoxy-2-[4-(3-methylisoxazole-4-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0846] A solution of 3-methylisoxazole-4-carbonyl chloride (1.01 g., 6.9mmole) in dioxane and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline(2.00 g., 6.9 mmole) in dioxane was stirred under reflux for 15 hours,then worked up as described in Example 1. The title compound afterrecrystallization from methanol had a mp. of 300°-301° C. withdecomposition.

[0847] Anal. Calcd. for C₁₉H₂₂N₆O₄HCl: C, 52.47; H, 5.33; N, 19.33.Found: C, 52.62; H, 5.31; N, 19.12 (corrected for 1.13% H₂O).

Example 994-Amino-6,7-dimethoxy-2-[4-(3-methylisoxazole-5-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0848] A solution of 3-methylisoxazole-5-carbonyl chloride (0.73 g.,5.02 mmole) in dioxane was added to a solution of4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.45 g., 5.02 mmole)in dioxane. The mixture was heated briefly, then was stirred at 20° C.for 2.5 hours. Workup as in Example 1 gave the title compound having am.p. of 263°-264° C. with decomposition.

[0849] Anal. Calcd. for C₁₉H₂₂N₆O₄HCl: C, 52.47; H, 5.33; Cl, 8.15; N,19.33. Found: C, 51.82; H, 5.04; Cl, 8.36; N, 19.46 (corrected for 4.82%H₂O).

Example 1004-Amino-6,7-dimethoxy-2-[4-(oxazole-4-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0850] A solution of oxazole-4-carbonyl chloride (0.73 g., 5.53 mmole)in dioxane was added to a solution of4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.60 g., 5.53 mmole)in dioxane. The mixture was heated at reflux for 0.5 hour, then wasstirred at 20° C. for 64 hours. Filtration gave the title compoundhaving a m.p. of 291°-294° C. with decomposition after recrystallizationfrom aqueous ethanol.

[0851] Anal. Calcd. for C₁₈H₂₀N₆O₄HCl H₂O: C, 49.26; H, 5.28; Cl, 8.08;N, 19.15. Found: C, 48.92; H, 4.83; Cl, 8.33; N, 18.94.

Example 1014-Amino-6,7-dimethoxy-2-[4-(2-methyloxazole-4-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0852] A solution of 2-methyloxazole-4-carbonyl chloride (1.01 g., 6.9mmole) in dioxane was added to a solution of4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.00 g., 6.9 mmole)in dioxane. The mixture was heated at reflux for 2 hours. Filtrationgave the title compound having a m.p. of 278°-280° C. with decompositionafter recrystallization from methanol.

[0853] Anal. Calcd. for C₁₉H₂₂N₆O₄HCl: C, 52.47; H, 5.33; N, 19.33.Found: C, 52.08; H, 5.43; N, 18.89 (corrected for moisture).

Example 1024-Amino-6,7-dimethoxy-2-[4-(4-methyloxazole-5-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0854] The title compound was prepared from 4-methyloxazole-5-carbonylchloride (0.85 g.) and4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.68 g.) followingthe procedure of Example 1. The product had a m.p. of 283.5°-288° C.with decomposition.

[0855] Anal. Calcd. for C₁₉H₂₂N₆O₄HCl: C, 52.48; H, 5.33; Cl, 8.15; N,19.33. Found: C, 52.19; H, 4.94; Cl, 8.13; N, 19.05 (corrected for 1.59%H₂O).

Example 1034-Amino-6,7-dimethoxy-2-[4-(isothiazole-4-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0856] The title compound was prepared from isothiazole-4-carbonylchloride (1.01 g.) and4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.99 g.) followingpreviously described procedures. The product had a mp. of 286°-287° C.with decomposition.

[0857] Anal. Calcd. for C₁₈H₂₀N₆O₃S HCl: C, 49.48; H, 4.84; Cl, 8.11; N,19.23; S, 7.34. Found: C, 49.29; H, 4.81; Cl, 8.19; N, 19.27; S, 7.23(corrected for 0.93% H₂O)

Example 1044-Amino-6,7-dimethoxy-2-[4-(thiazole-2-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0858] The title compound was prepared from thiazole-2-carbonyl chloride(0.79 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.54g.) following previously described procedures. The product had a m.p. of273°-276° C. with decomposition.

[0859] Anal. Calcd. for C₁₈H₂₀N₆O₃S HCl: C, 49.48; H, 4.84; N, 19.23.Found: C, 48.68; H, 4.62; N, 18.87 (corrected for 4.19% H₂O).

Example 1054-Amino-6,7-dimethoxy-2-[4-(thiazole-4-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0860] The title compound was prepared from thiazole-4-carbonyl chloride(1.02 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.00g.) following previously described procedures. The product had a m.p. of274°-277° C. with decomposition.

[0861] Anal. Calcd. for C₁₈H₂₀N₆O₃S HCl: C, 49.48; H, 4.48; N, 19.24.Found: C, 49.11; H, 4.69; N, 19.31 (corrected for 4.47% H₂O).

Example 1064-Amino-6,7-dimethoxy-2-[4-(2-methylthiazole-4-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0862] The title compound was prepared from 2-methylthiazole-4-carbonylchloride (0.49 g.) and4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.87 g.) followingpreviously described procedures. The product had a m.p. of 260°-263° C.with decomposition.

[0863] Anal. Calcd. for C₁₉H₂₂N₆O₃S HCl: C, 50.60; H, 5.14; N, 18.64.Found: C, 50.88; H, 4.96; N, 18.67 (corrected for 2.88% H₂O).

Example 1074-Amino-6,7-dimethoxy-2-[4-(thiazole-5-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0864] The title compound was prepared from thiazole-5-carbonyl chloride(0.77 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.51g.) following previously described procedures. The product had a m.p. of280°-281° C. with decomposition.

[0865] Anal. Calcd. for C₁₈H₂₀N₆O₃S HCl: C, 49.48; H, 4.84; Cl, 8.11; N,19.23; S, 7.34. Found: C, 49.22; H, 5.19; Cl, 8.31; N, 19.49; S, 6.79(corrected for 2.63% H₂O).

Example 1084-Amino-6,7-dimethyoxy-2-[4-(2-methylthiazole-5-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0866] The title compound was prepared from 2-methylthiazole-5-carbonylchloride (0.42 g.) and4-amino-6,7-dimethyoxy-2-(1-piperazinyl)-quinazoline (0.75 g.) followingpreviously described procedures. The product had a m.p. of 294°-297° C.with decomposition.

[0867] Anal. Calcd. for C₁₉H₂₂N₆O₃S HCl: C, 50.60; H, 5.14; N, 18.64.Found: C, 50.60; H, 4.95; N, 18.50 (corrected for 1.96% H₂O).

Example 1094-Amino-6,7-dimethoxy-2-[4-(4-methylthiazole-5-carbonyl)-piperazin-1-yl]quinazolineHydrochloride

[0868] The title compound was prepared from 4-methylthiazole-5-carbonylchloride (1.1 g.) and4-amino-6,7-dimethyoxy-2-(1-piperazinyl)quinazoline (2.0 g.) followingpreviously described procedures. The product had a m.p. of 293°-295° C.with decomposition.

Example 110 Synthesis of 2-[N⁴- (2-furoyl) -homopiperazinol-4-amino-6,7-dimethoxy-quinazoline: a. Synthesis of2-homopiperazino-4-amino-6,7-dimethoxy-quinazoline:

[0869] 17 Grams of 2-chloro-4-amino-6,7-dimethoxy-quinazoline and 18.2 gof N-formylhomopiperazine are added to 170 ml of butanol and the wholeis refluxed with stirring for three hours. After completion of thereaction, the mixture is cooled, and the crystals thus precipitated arefiltered out, washed with a small quantity of ethanol and air-dried. 25Grams of crude crystal are obtained. 13 Grams of the crystal thusobtained are taken and added with 80 ml of 9% hydrochloric acid. Themixture is refluxed under stirring for 60 minutes. After completion ofthe reaction, the mixture is allowed to cool. The crystal thusprecipitated are filtered out and then recrystallized from a mixture ofmethanol and ethanol.

[0870] Yield: 10.7 g (80.4%)

[0871] Melting point: 246-247° C.:

[0872] Elementary analysis (as C₁₈H₂₁n₅O₂-2HCl ½ H₂O): C H N Theoretical(%) 46.74 6.29 18.17 Found (%) 46.44 6.40 17.90

b. Synthesis of2-[N⁴-(2-furoyl)-homopiperazino]-4-amino-6,7-dimethoxy-quinazoline:

[0873] A solution of 3 g of2-homopiperazino-4-amino-6,7-dimethoxy-quinazoline in 60 ml of acetoneis added dropwise to a solution of 1.3 g of 2-furancarboxylic acidchloride in 30 ml of acetone under stirring and ice-cooling. Aftercompletion of the addition, the stirring is continued for additional onehour to complete the reaction. The crystals thus precipitated arefiltered out and recrystallized from a mixture of methanol and ethanol.

[0874] Yield: 3.1 g (70.4%)

[0875] Melting point: 278-280° C.

[0876] Elementary analysis (as C₂₀H₂₃N₃O₄ HCl): C H N Theoretical (%)55.36 5.59 16.15 Found (%) 55.30 5.45 16.18

Example 111 Synthesis of2-(N⁴-homopiperazino)-4-amino-6,7-dimethoxy-quinazoline:

[0877] 2 Grams of triethylamine are added to a solution of 1.5 g of2-homopiperazino-4-amino-6,7-dimethoxy-quinazoline and 1.5 g of α-butylchloride in 20 ml of n-butanol and the mixture is refluxed understirring for 24 hours. After completion of the reaction, the solvent isdistilled off and then the thus obtained residue is made alkaline byaddition of 10% aqueous caustic soda solution. The oily substance thusseparated out is extracted with chloroform. The extract is washed withwater, dried with potassium carbonate and filtered. The filtrate isconcentrated. The residue thus obtained is dissolved in 30 ml ofisopropanol. The solution is added with 3 ml of saturated isopropanol/hydrochloric acid and the resulting crystals are filtered out andrecrystallized from a mixture of methanol/ethanol. The aimed compound isobtained as dihydrochloride.

[0878] Yield: 0.9 g (50.6%)

[0879] Elementary analysis (as C₁₀H₂₃N₂O₄-2HCl-½ H₂O) C H N Theoretical(%) 51.68 7.32 15.86 Found (%) 51.74 7.13 16.42

Examples 112 to 126

[0880] Various compounds shown in Table 1 were obtained by the methodssimilar to those used in Examples 110 and 111.

[0881] The results are summarized in Table 1. TABLE 1 Elementaryanalyais (%) Molecular formula Theoretical Example A M.P. (° C.) Found112 C₁₇H₁₉N₃O₃—HCl—H₂O 51.05 6.57 17.52 235-240 51.16 6.34 17.8 113C₁₉H₁₇N₃O₃—HCl—½H₂O 54.46 6.99 16.71 240-250 54.20 6.97 17.18 114C₁₉H₁₇N₃O₃—HCl 55.66 6.90 17.09 280-282 55.40 6.89 16.79 115C₂₃H₂₄ClN₃O₃—HCl—H₂O 53.22 5.49 14.11 235-240 53.18 5.79 13.61 116C₂₃H₂₇N₃O₄—HCl 58.27 5.97 14.78 225-235 57.78 6.09 14.32 117C₂₃H₂₇N₂O₁S—HCl 52.91 5.42 13.42 270-272 52.98 5.44 13.45 118C₂₄H₂₈N₂O₃—HCl—½H₂O 56.18 6.10 13.65 220-225 56.06 6.29 13.46 119C₉₄H₉₇N₃O₃—HCl—H₂O 59.06 6.21 14.35 210-215 58.65 5.82 14.20 120C₂₄H₂₂N₃O₃—HCl—H₂O 55.17 5.61 13.41 245-250 55.62 5.46 13.83 121C₂₃H₂₉N₃O₃—HCl—½H₂O 57.51 5.42 13.42 235-240 57.80 5.62 13.52 122C₂₇H₃₁N₂O₂—HCl—½H₂O 57.18 5.88 12.35 292-294 57.52 6.06 12.41 123C₁₀H₂₂N₂O₂ 60.54 7.32 22.07 208-210 60.37 7.22 22.07 124C₂₂H₂₂Cl₂N₂O₂—2HCl 49.35 5.09 13.08 240-245 49.44 5.56 12.52 125C₂₂H₂₂N₂O₂—2HCl 55.63 6.31 14.11 280-285 55.59 6.36 14.34 126C₂₂H₂₂N₂O₂—3HCl 51.01 6.04 16.23 250-260 50.52 6.30 15.90

Example 1274-Amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

[0882] a. A mixture of N-(cyclopentylcarbonyl) piperazine (3.6 g., 0.02mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (4.79 g., 0.02 mole)in 50 ml. of absolute ethanol is heated in an enclosed reactor at 170°C. for a period of 16 hours. The reaction mixture is cooled, filteredand insolubles triturated with 100 ml. of concentrated ammoniumhydroxide to provide the free base. The insoluble product is collectedand crystallized from methanol to afford analytically pure4-amino-2-[4-cy-clopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquina-zoline,m.p. 256.0° C. (corr.).

[0883] Analysis. Calcd. for C₂₀H₂₇N₅O₃ (percent): C, 62.32; H, 7.06; N,18.17. Found (percent): C, 62.06; H, 7.24; N, 17.99.

[0884] Example 127(a) illustrates the procedure of Equation 1 of U.S.Pat. No. 4,060,615 to Matier et al., which is incorporated herein byreference, while the following Examples 127(b-e) illustrate proceduresof Equations 2-5 of U.S. Pat. No. 4,060,615, respectively, for thepreparation of4-amino-2-[4-(cyclopentyl-carbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.

[0885] b. Cyclopentylcarbonyl chloride (0.1 mole) is added to 0.1 moleof 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline in 300 ml. ofmethanol with vigorous stirring at room temperature. Stirring iscontinued for a period of 2 to 6 hours and the product is isolatedaccording to the procedure of Example 127(a) to provide4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.If the hydrochloride salt is desired, the base treatment is omitted andevaporation of the solvent provides4-amino-2-[4-(cyclopentylcarbonyl)-piperazinyl]-6,7-dimethoxyquinazolinehydrochloride, m.p. 279°-280° C. (dec.) (corr.) crystallized frommethanol-isopropanol.

[0886] Analysis. Calcd. for C₂₀H₂₇N₅O₃.HCl (percent): C, 56.93; H. 6.69;N, 16.60. Found (percent): C, 56.65; H. 6.89; N. 16.44.

[0887] c. A mixture of anhydrous ammonia and4-chloro-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolinein 100 ml. of tetrahydrofuran is heated at 100° C. for a period of 16 to24 hours and the product isolated according to the procedure of Example127(a) to provide4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.

[0888] d. A mixture of 4-amino-2-methylmercapto-6,7-dimethoxyquinazoline(0.1 mole) and from 0.1 to 0.15 mole ofN-(cyclopentylcarbonyl)piperazine in 150 ml. of isoamyl alcohol isrefluxed for a period of 8 to 24 hours. The solvent is evaporated andresidual material, treated according to procedure of Example 127(a),provides4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.

[0889] e. Ethyl-4-(cyclopentylcarbonyl)piperazin-1-yl-for-mamidatehydrochloride (0.01 mole) is added to a solution of4,5-dimethoxy-2-aminobenzonitrile (0.01 mole) in 30 ml. ofN,N-dimethylformamide. Sodium hydride (0.02 mole of a 56% suspension inmineral oil) is added and the mixture stirred 0.5 hr. at roomtemperature and then at 100° C. for a period of 12 hr. When the reactionperiod is complete, water is added providing4-amino-2-[4-cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.

Example 1284-Amino-2-[4-(cyclopropylcarbonyl)-1-pinerazinyl]-6,7-dimethoxyquinazoline

[0890] N-(Cyclopropylcarbonyl)piperazine (3.08 g., 0.02 mole) and2-chloro-4-amino-6,7-dimethoxyquinazoline (4.74 g., 0.02 mole) arereacted according to the procedure of Example 127(a). The crude productcrystallized from ethanol affords analytically pure4-amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline,m.p. 283.5° C. (corr.).

[0891] Analysis, Calcd. for C₁₈H₂₃N₅O₃ (percent): C, 60.49; H, 6.49; N,19.59. Found (percent): C, 60.56; H, 6.46; N, 19.41.

Example 1294-Amino-2-[4-(cyclohexylcarbonyl)-1-piperazinyll-6,7-dimethoxyquinazoline

[0892] N-(Cyclohexylcarbonyl)piperazine (5.9 g., 0.03 mole) and2-chloro-4-amino-6,7-dimethoxyquinazoline (7.2 g., 0.03 mole) arereacted according to the procedure of Example 127(a). The crude productcrystallized from methanol affords analytically pure 4-amino-2-[4-(cyclohexylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p.223°-225° C., resolidifying and remelting at 248.0°-250.0° C. (corr.)

[0893] Analysis. Calcd. for C₂₁H₂₉N₅O₃ (percent): C, 63.14; H, 7.32; N,17.53. Found (percent): C, 63.07; H, 7.43; N, 17.63.

Example 1304-Amino-2-[4-(cyclopenten-1-ylcarbonyl)-piperazinyl]-6,7-dimethoxyquinazoline

[0894] N-(1-cyclopenten-1-ylcarbonyl)piperazine (1.8 g., 0.01 mole) and2-chloro-4-amino-6,7-dimethoxyquinazoline (2.4 g., 0.01 mole) arereacted according to the procedure of Example 127(a). The isolatedproduct crystallized from methanol affords analytically pure4-amino-2-[4-(1-cyclopenten-1-ylcarbonyl)piperazinyl]-6,7-dimethoxyquinazoline,m.p. 256.5°-258.0° C. (corr.).

[0895] Analysis. Calcd. for C₂₀H₂₅N₅O₃ (percent): C, 62.65; H, 6.57; N,18.26. Found (percent): C, 65.23; H, 6.56; N, 18.42.

Example 1314-Amino-2-[4-(3-cyclopentenylcarbonyl)-1-piperazinyl-6,7-dimethoxyquinazoline

[0896] N-(3-cyclopentenylcarbonyl)piperazine (2.7 g., 0.015 mole) and2-chloro-4-amino-6,7-dimethoxyquin-azoline (3.6 g., 0.015 mole) arereacted according to the procedure of Example 127(a). The crude productcrystallized from methanol affords analytically pure4-amino-2-[4-(3-cyclopentenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline,m.p. 215.5°-217.5° C. (corr.).

[0897] Analysis. Calcd. for C₂₀H₂₅N₅O₃ (percent): C, 62.65; H, 6.57; N,18.26. Found (percent): C, 62.35; H, 6.72; N, 18.21.

Example 132 4-Amino-2-[4-(3-cyclohexenylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline

[0898] N-(3-cyclohexenylcarbonyl)piperazine (7.65 g., 0.04 mole) and2-chloro-4-amino-6,7-dimethoxyquinazoline (9.6 g., 0.04 mole) arereacted according to the procedure of Example 127(a). The crude productcrystallized from methanol affords analytically pure4-amino-2-[4-(3-cyclohexenlcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline,m.p. 211°-213° C. resolidifying and melting at 234.0°-236.0° C. (corr.).

[0899] Analysis. Calcd. for C₂₁H₂₇N₅O₃ (percent): C, 63.46; H, 6.85; N,17.62. Found (percent): C, 63.18; H, 6.80; N, 17.63.

Example 1334-Amino-2-[4-(cyclobutylcarbonyl)-1-piperazinyl]-6,7-dimethyxyquinazolineHydrochloride

[0900] N-(Cyclobutylcarbonyl)piperazine (0.02 mole) and2-chloro-4-amino-6,7-dimethoxyquinazoline (0.02 mole) are reactedaccording to the procedure of Example 127(a). When reaction is complete,the solvent is removed and the residue crystallized frommethanolisopropanol to provide analytically pure4-amino-2-[4-(cyclobutylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolinehydrochloride hydrate, m.p. 267°-268° C. (dec.) (corr.).

[0901] Analysis. Calcd. for C₁₉H₂₅N₅O₃.HCl.¼H₂O (percent): C, 55.33; H,6.48; N, 16.98. Found (percent): C, 55.49; H, 6.75; N. 16.62.

Example 1344-Amino-2-[4-(cycloheptylcarbonyl)-1-piperazinyl]-6,7-dimethoxyqinazolineHydrochloride

[0902] N-(Cycloheptylcarbonyl)piperazine (0.02 mole) and2-chloro-4-amino-6,7-dimethoxyquinazoline (0.02 mole) are reactedaccording to the procedure of Example 133. Crystallization of theproduct from methanol-isopropanol provides analytically pure4-amino-2-[4-(cycloheptylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolinehydrochloride, m.p. 278°-279° C. (corr.).

[0903] Analysis. Calcd. for C₂₂H₃₁N₅O₃.HCl (percent): C, 58.72; H, 7.17;N, 15.56. Found (percent): C, 58.73; H, 7.39; N, 15.44.

Example 135

[0904] Following the procedure of Example 127 but employing an equimolaramount of: N-(2-cyclopentenylcarbonyl)piperazine,N-(1-cyclohexen-1-ylcarbonyl)piperazine,(1-cyclohexen-1-ylcarbonyl)piperazine, N-(cyclooctylcarbonyl)piperazine,N-(2-methylcyclopentylcarbonyl)piperazine,N-(1-methylcyclopentylcarbonyl)piperazine,N-(1-methylcyclohexylcarbonyl)piperazine, in place ofN-(cyclopentylcarbonyl)piperazine, there is produced:

[0905] a.4-amino-2-[4-(2-cyclopentenylcarbonyl)1-pipera-zinyl]-6,7-dimethoxyquinazoline.

[0906] b.4-amino-2-[4-(1-cyclohexen-1-ylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline,

[0907] c.4-amino-2-[4-(cyclooctylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline,

[0908] d.4-amino-2-[4-(2-methylcyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.

[0909] e.4-amino-2-[4-(1-methylcyclopentylcarbonyl)-1-piperazinyl3-6,7-dimethoxyquinazoline,

[0910] f.4-amino-2-[4-(1-methylcyclohexylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.

Example 1364-Hydrazino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolineHydrochloride

[0911] N-(Cyclopentylcarbonyl)piperazine (0.02 mole) and2-chloro-4-hydrazino-6,7-dimethoxyquinazoline (0.02 mole) reactedaccording to the procedure of Example 133 provides4-hydrazino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolinehydrochloride,m.p. 282°-284° C.

Example 137

[0912] Suspensions

[0913] A suspension of4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolineor a pharmaceutically acceptable salt thereof is prepared with thefollowing ingredients:

[0914] Active ingredient: 20 g.

[0915] Sucrose, U.S.P.: 400 g.

[0916] Sorbitol, U.S.P.: 100 g.

[0917] Bentonite: 20 g.

[0918] Flavors, q.s.

[0919] Water, distilled to make 1 liter

[0920] Each milliliter of the suspension contains approximately 20 mg.of the active ingredient.

Example 138

[0921] Tablets

[0922] The following ingredients are blended in the proportion by weightindicated according to conventional pharmaceutical techniques to providea tablet base:

[0923] Lactose: 79

[0924] Corn Starch: 10

[0925] Talcum: 6

[0926] Tragancanth: 4

[0927] Magnesium Stearate: 1

[0928] This tablet base is blended with sufficient4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolineor a pharmaceutically acceptable salt thereof to provide tabletscontaining 0.1, 0.25, 0.5, 1, 2.5, 5, 7.5, 10, 25, and 50 mg. of activeingredient; formed in a tablet of the desired size in a conventionaltablet press.

Example 139

[0929] Dry Filled Capsules

[0930] The following ingredients are blended in a conventional manner inthe proportion by weight indicated.

[0931] Lactose, U.S.P.: 50

[0932] Starch: 5

[0933] Magnesium Stearate: 2

[0934] Sufficient4-amino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolineor a pharmaceutically acceptable salt thereof is added to the blend toprovide capsules containing 0.1, 0.25, 0.5, 1, 2.5, 5, 7.5, 10, 25, and50 mg. of active ingredient, and filled into hard gelatin capsules of asuitable size.

[0935] It will be understood that various changes and modifications canbe made in the details of procedure, formulation and use withoutdeparting from the spirit of the invention, especially as defined in thefollowing claims.

We claim:
 1. A method of treating a patient having precancerous lesionssensitive to compounds below and in the need of treatment, comprisingadministering to the patient a pharmacologically effective amount of acompound of the formula:

wherein R1, R2, R3 and R4, each of which may be the same or different,are selected from a hydroxyalkyl group, an acylamino group, a carboxylgroup which may be protected, or two of R1, R2, R3 or R4 may togetherform methylenedioxy, ethylenedioxy, or a phenyl ring; R5 and R6, each ofwhich may he the same or different, are selected from a hydrogen atom, alower alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl grouphaving from 1 to 6 carbon atoms, an aminoalkyl grouid having from 1 to 6carbon atoms, a carboxyalkyl group which may be protected, analkylcarbamoyl group having 2 to 8 carbon atoms, a 1,3-benzdioxolyalkylgroup or 1,4-benzdioxylalkyl group, or further R5 and R6 may form a ringwhich may contain another nitrogen atom and/or oxygen atom together withthe nitrogen atom to which they are bonded, which may be substituted; R7is selected from an acyl group, an alkoxyalkyl group having 2 to 8carbon atoms, a carboxyalkyl group having 2 to 8 carbon atoms which maybe protected or a hydroxyalkyl group having 2 to 8 carbon atoms; R8 isselected from a hydrogen atom, a hydroxyl group, a carboxyl group whichmay be protected, a cyano group, an acyl group, a heteroaryl group whichmay be substituted, said substitutions, which may be the same ordifferent, are selected from a hydrogen atom, a halogen atom, a hydroxylgroup, an amino group, a nitro group, an alkyl group having from 1 to 6carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, analkoxyalkyl group having from 2 to 8 carbon atoms, an alkenyl grouphaving from 2 to 8 carbon atoms, an acyl group, an acylamino group, analkylsulfonylamino group, a hydroiminoalkyl group, analkyloxy-carbonylamino group, an alkyloxybarbonyloxy group or aheteroaryl group which may be substituted; or two of said substitutionsmay together form a saturated or unsaturated ring which may contain anitrogen, a sulfer atom or an oxygen atom; and Y is a group representedby the formula —(CH2)q— (wherein q is 0 or an integer of 1 to 8), when qis an integer of 1 to 8, each carbon atom may have from 1 to 2substituents, or Y is a group represented by the formula:


2. The method of claim 1 , wherein R1, R2, R3, and R4, each of which maybe the same or different from one another, are selected from a hydrogenatom, a cyano group, a halogen atom, or a lower alkoxy group.
 3. Themethod of claim 2 , wherein one of R1, R2, R3 and R4 is a cyano group, ahalogen atom or a methoxy group.
 4. The method of claim 3 , wherein R2is a halogen atom.
 5. The method of claim 4 , wherein R2 is a chlorineatom.
 6. The method of claim 5 , wherein R1, R3 and R4 are hydrogenatoms.
 7. The method of claim 6 , wherein Y is a group represented bythe formula —(CH2)q—, wherein q is an integer of 1 to
 8. 8. The methodof claim 7 , wherein R8 is benzyl group which may be substituted, saidsubstitutions, each of which may be the same or different, are eachselected from a hydrogen atom, a halogen atom, a hydroxy group, an aminogroup, a nitro group, a lower alkyl group, a lower alkoxy group, a loweralkoxyalkyl group, a lower alkenyl group, an acyl group, an acylaminogroup, an alkylsulfonylamino group, a hydroxyiminoalkyl group, analkyloxycarbonylamino group, an alkyloxycarbonyloxy group or aheteroaryl group which may be substituted, or two of the substitutionsmay together form a saturated or unsaturated ring which may contain anitrogen atom, a sulfer atom or an oxygen atom; and q is an integer of 1to
 8. 9. The method of claim 8 , wherein R8 is a group represented bythe formula:


10. The method of claim 9 , wherein R7 is a hydrogen atom.
 11. Themethod of claim 10 , wherein R5 and R6 form a ring represented by theformula:

wherein R9 is selected from a hydroxyl group which may be protected, ahalogen atom, a alkyl group having 1 to 8 carbon atoms, a lower alkoxygroup, a carboxyl group which may be protected, a hydroxyalkyl group, acarboxyalkyl group and a heteroacyl group.
 12. The method of claim 10 ,wherein said compound is2-(4-Carboxyiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-choroquinazolin.
 13. The method of claim 1 , wherein Y is agroup represented by the formula —(CH2)q—, wherein q is an integer of 1to
 8. 14. The method of claim 13 , wherein R8 is a group represented bythe formula:


15. The method of claim 14 , wherein one of R1, R2, R3 and R4 is a cyanogroup, a chlorine atom or a methoxy atom.
 16. The method of claim 15 ,wherein R2 is a halogen atom.
 17. The method of claim 16 , wherein R2 isa chlorine atom.
 18. The method of claim 17 , wherein R1, R3 and R4 arehydrogen atoms.
 19. The method of claim 18 , wherein R5 and R6 form aring which is represented by the formula:

wherein R9 is selected from a hydroxyl group which may be protected, ahalogen atom, a alkyl group having 1 to 8 carbon atoms, a lower alkoxygroup, a carboxyl group which may be protected, a hydroxyalkyl group, acarboxyalkyl group and a heteroacyl group.
 20. The method for inhibitingthe growth of neoplastic cells sensitive to a compound below, comprisingexposing said cells to an effective amount of a compound of the formula:

wherein R1, R2, R3 and R4, each of which may be the same or different,are selected from a hydroxyalkyl group, an acylamino group, a carboxylgroup which may be protected, or two of R1, R2, R3 or R4 may togetherform methylenedioxy, ethylenedioxy, or a phenyl ring; R5 and R6, each ofwhich may be the same or different, are selected from a hydrogen atom, alower alkyl group having 1 to 6 carbon atoms, a hydroxyalkyl grouphaving from 1 to 6 carbon atoms, an aminoalkyl group having from 1 to 6carbon atoms, a carboxyalkyl group which may be protected, analkylcarbamoyl group having 2 to 8 carbon atoms, a 1,3-benzdioxolyalkylgroup or 1,4-benzdioxylalkyl group, or further R5 and R6 may form a ringwhich may contain another nitrogen atom and/or oxygen atom together withthe nitrogen atom to which they are bonded, which may be substituted; R7is selected from an acyl group, an alkoxyalkyl group having 2 to 8carbon atoms, a carboxyalkyl group having 2 to 8 carbon atoms which maybe protected or a hydroxyalkyl group having 2 to 8 carbon atoms; R8 isselected from a hydrogen atom, a hydroxyl group, a carboxyl group whichmay be protected, a cyano group, an acyl group, a heteroaryl group whichmay be substituted, said substitutions, which may be the same ordifferent, are selected from a hydrogen atom, a halogen atom, a hydroxylgroup, an amino group, a nitro group, an alkyl group having from 1 to 6carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, analkoxyalkyl group having from 2 to 8 carbon atoms, an alkenyl grouphaving from 2 to 8 carbon atoms, an acyl group, an acylamino group, analkylsulfonylamino group, a hydroiminoalkyl group, analkyloxy-carbonylamino group, an alkyloxybarbonyloxy group or aheteroaryl group which may be substituted; or two of said substitutionsmay together form a saturated or unsaturated ring which may contain anitrogen, a sulfer atom or an oxygen atom; and Y is a group representedby the formula —(CH2)q— (wherein q is 0 or an integer of 1 to 8), when qis an integer of 1 to 8, each carbon atom may have from 1 to 2substituents, or Y is a group represented by the formula:


21. The method of claim 20 wherein R1, R2, R3 and R4 may independentlybe a cyano group, a halogen or a methoxy group.
 22. The method of claim21 , wherein R2 is a halogen.
 23. The method of claim 22 , wherein R8 isrepresented by the formula:


24. The method of claim 23 , wherein R5 and R6 form a ring which isrepresented by the formula:


25. The method of claim 24 , wherein said compound is2-(4-Carboxyiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazolin.
 26. The method of claim 21 wherein R7 and R8are each hydrogen; q is zero; and R5 and R6 form a substituted ringrepresented by the structure:

and R10 is hydrogen, amino, lower alkyl group, or NHCO2R11 in which R11is a lower alkyl group.
 27. The method of regulating apoptosis in humancells, comprising exposing said cells to an effective amount of acompound of formula:

wherein R1, R2, R3 and R4, each of which may be the same or different,are selected from a hydrogen atom, a alkoxy group having from 1 to 6carbon atoms, a hydroxyalkyl group, a cyano group, an acylamino group, acarboxyl group which may be protected or two of R1, R2, R3 or R4 maytogether form methylenedioxy, ethylenedioxy, or a phenyl ring; R5 andR6, each of which may be the same or different, are selected from ahydrogen atom, a lower alkyl group having 1 to 6 carbon atoms, ahydroxylakyl group having from 1 to 6 carbon atoms, an aminoalkyl grouphaving from 1 to 6 carbon atoms, a carboxyalkyl group which may beprotected, alkylcarbamoyl group having 2 to 8 carbon atoms, a1,3-benzdioxolyalkyl group or a 1,4-benzdioxylalkyl group, or further R5and R6 may form a ring which may contain another nitrogen atom and oroxygen atom together with the nitrogen atom to which they are bonded,and which may be substituted; R7 is selected from a hydrogen atom, aalkyl group having 1 to 6 carbon atoms, an acyl group, a alkoxyalkylgroup having 2 to 8 carbon atoms, a carboxyalkyl group having 2 to 8carbon atoms which may be protected or a hydroxyalkyl group having 2 to8 carbon atoms; R8 is selected from a hydrogen atom, a hydroxyl group, acarboxyl group which may be protected, a cyano group, an acyl group, aheteroaryl group which may be substituted or a benzyl group which may besubstituted, said substitutions, which may be the same or different, areselected from a hydrogen atom, a halogen atom, a hydroxyl group, anamino group, a nitro group, a alkyl group having from 1 to 6 carbonatoms, a alkoxy group having from 1 to 6 carbon atoms, a alkoxyalkylgroup having from 2 to 8 carbon atoms, a alkenyl group having from 2 to8 carbon atoms, an acyl group an acylamino group, an alkylsulfonylaminogroup, a hydroiminoalkyl group, an alkyloxy-carbonylamino group, analkyloxybarbonyloxy group or a heteroaryl group which may besubstituted: or two of said substitutions may together from a saturatedor unsaturated ring which may contain a nitrogen, a sulfer atom or anoxygen atom; and Y is a group represented by the formula —(CH2)q—(wherein q is 0 or an integer of 1 to 8), when q is an integer of 1 to8, each carbon atom may have from 1 to 2 substituents, or Y is a grouprepresented by the formula:


28. The method of claim 26 , wherein R2 is a halogen.
 29. The method ofclaim 27 , wherein R8 is represented by the formula:


30. The method of claim 28 , wherein R5 and R6 form a ring which isrepresented by the formula:


31. The method of claim 29 , wherein said compound is2-(4-Carboxypiperidino) -4- (3,4-methylenedioxybenzyl)amino-6-chloroquinazolin.